IE 1 (Med Chem: Kaur)

Thiazides Structure

• Sulphonamide

• Benzo (phenol ring)

• 2N position: Alkyl substitution

• Position 3: Lipophilic group

• Position 6: EWG

• Two fused rings

• 3,4-dihydro derivative

T/F: Sulphonamide is basic.

F → Acidic

T/F: Salt is more water soluble compared to an acid or base.

T

What’s the SAR at position 7?

Replacement or removal of the sulfonamide group at position 7 yields compounds with little or no diuretic activity

What’s the SAR at position 6?

An EWG is necessary at position 6 for diuretic activity

What’s the SAR with the 3,4-dihydro derivative?

Saturation of the double bond to give a 3,4-dihydro derivative produces a diuretic 10x more active than the unsaturated derivative

What’s the SAR with position 3?

Substitution with a lipophilic group at position 3 increases diuretic potency

Haloalkyl, araalkyl, thioether substitution increases lipid solubility of molecule and yields compounds with longer duration of action

What’s the SAR with position 2?

Alkyl substitution on the 2-N position decreases polarity and increases duration of diuretic action

T/F: Furosemide has a greater diuretic potency than Bumetanide.

F → Bumetanide does!

T/F: For acidic groups, the smaller the pKa, the stronger the acid is.

T

What drug class are these drugs apart of?

What are these and what drug has each of these structures?

Heterocytes

T/F: When comparing basic functional groups, the lower the pKa, the stronger the base.

F → Higher the pKa

What are the functional groups involved in Triamterene and Amiloride?

Triamterene vs. Amiloride: Which has a longer half-life and is more potent?

Amiloride

What drug class do these drugs belong to?

K-sparing diuretics

What drug class are these drugs apart of?

Spironolactone vs. Eplerenone: Which one has a greater affinity for the mineralcorticoid receptor? Which one is more selective?

• Spironolactone: Greater affinity

• Eplerenone: More selective aldosterone antagonist w/ limited or no inhibitory effects on GR and PR

Spironolactone vs. Eplerenone: Which one has fewer sexual side effects?

Eplerenone

The more lipophilic drugs are primarily cleared by the (), whereas the more hydrophilic agents are cleared by the ().

Liver

Kidney

What class of drugs are these apart of? Which one is non-selective? Which one is selective?

B-Blockers: Aryloxypropanolamines

LEFT: Non-selective (Propranolol)

RIGHT: B1-Selective Antagonist (Atenolol, Esmolol)

Which drug has a LONGER half-life: Propranolol vs Atenolol/Esmolol?

Propranolol

Why does Esmolol have short half-life?

Methyl ester of a carboxylic acid (4-substituted aryloxypropanolamine) → makes it susceptible to hydrolysis by serum esterases

Rank the drug from shortest to longest half-life.

What is the structure for an selective a-1 adrenergic antagonists?

4-amino-6,7-dimethoxyquinazoline attached to a piperazine ring

Carvedilol has a _ properties.

Antioxidant

T/F: Labetalol and Carvedilol are both racemic mixtures.

T

T/F: Labetalol has greater A1 blocking activity than B-blocking

F

Which heterocyte is involved in this structure and what drug class are these structures apart of?

Carbazole

Mixed A & B blocker

Which drug is this?

Nifedipine

Phenylalkylamine + Benzothiazepine

Verapamil + Diltiazem

() is essential for CCB activity

1,4-DHP ring

T/F: Only ortho substitution of CCB phenyl ring gives optimal activity.

F → Ortho and para

() decreases CCB activity

Small nonplanar alkyl or cycloalkyl group decreases activity

What part of this structure helps salt form?

-NH (basic → keeps salt form)

What CCB was designed to have an ultra-short duration of action? `

Clevidipine

T/F: All CCBs possess good lipid solubility and oral absorption.

T

Verapamil and diltiazem both contain _

Teritary amines

What is Dilitazem metabolized to?

Desacetyl derivative

Name 3 Class IA Antiarrhytmic Drugs

1. Quinidine

2. Procainamide

3. Disopyramide

What family is a Quinidine member?

Alkaloids

What is quinidine composed of?

Quinoline ring + bicyclic quinuclidine ring

In special situations, quinidine can be administered intravenously as the _.

Gluconate salt

T/F: Good absorption (~95%) after oral administration of the salt forms of quinidine.

T

Peak plasma levels of procainamide are observed within _ to _ minutes after oral administration, and approximately 70% to 80% of the dose is bioavailable.

45-90

T/F: Disopyramide is not rapidly and completely absorbed from the gastrointestinal tract.

F

Name 2 Class IB Antiarrhythmic Drugs

1. Lidocaine

   1. Mexiletine

What is the drug of choice for emergency treatment of ventricular arrhythmias?

Lidocaine

T/F: Lidocaine is effective as an antiarrhythmic only when given orally

F→ Parenterally

T/F: Hepatic metabolism of Lidocaine is slow

F → Rapid

Name 2 IC Antiarrhythmic Drugs

1. Flecainide

2. Propafenone

Name 2 Class II Antiarrhytmic Drugs

1. Propranolol (phenyloxypropanolamine)

2. Sotalol (methanesulfonanilide derivative)

Name 3 Class III Potassium Channel Blocker Drugs

Amiodarone

Dronedarone

Ibutilide

Dofetilide

What drug has a structural analog of thyroid hormone?

Amiodarone

T/F: Amiodarone is highly hydrophillic

F → Lipophilic

T/F: Amiodarone is eliminated extremely slowly

T

Major metabolite, (), is bioactive.

Desethylamiodarone

Dronedarone is the () derivative of amiodarone

Benzofuran noniodinated

T/F: Amiodarone is more lipophilic than dronedarone

T

T/F: Dronedarone has poor bioavailability after oral administration

T

Ibutilide is a () derivative

Methanesulfonanilide

Dofetilide is a bis-()

methanesulfonanilide derivative

Which drug is the most potent and selective Class III methanesulfonanilides?

Dofetilide

Name two Class IV calcium channel blockers

• verapamil

• dilitazem

What drug is the only oral positive ionotropic agent?

Digoxin (Cardiac Glycoside or Positive Ionotropic Drug)

What’s the basis for several for digoxin-drug interactions?

Alterations in P-gp transport

Phase 1 and Phase II Metabolism

Phase 1: Introduces a F.G (oxidation)

Phase 2: Attaches drug molecule (glucuronidation)

Enantiomers have identical physical and chemical properties except _

1. Ability to rotate the plane of polarized light

2. Rate of reaction and interaction with other chiral compounds and environments

What are enantiomers?

Nonsuperimposable mirror image

A single stereoisomer constitutes a () drug, whereas an equimolar mixture of stereoisomers is a () mixture.

Chiral

Racemic

T/F: There is no relation between optical rotation and configuration

T

Summarize the digoxin and quinidine interaction

Quinidine (P-gp substrate) binds to P-Gp pump → Digoxin concentration heavily increases to toxic levels

Quinidine is always used as a () form as as ()

Water soluble

Gluconate salt

T/F: Lidocaine is used orally.

F → Parenterally, IV

The _ group in Mexiletine is believed to slow the rate of metabolism and contribute to good oral activity.

A-methyl group

What are all the drugs with a methanesulfonamilide derivative?

• Sotalol (Class II Antiarrhythmic)

• Dofetilide (Class III Potassium Channel Blocker)

• Ibutilide (Class III Potassium Channel Blocker)

T/F: Amiodarone is highly lipophillic

T

The () groups of Amiodarone were removed to reduce toxic effects of Amiodarone on the () and other organs.

Iodine

Thyroid

In Droneadrone, the () group was added to reduce lipophilicity

Methylsulfonamido

What drug has a methanesulfonamide derivative and is used only as IV?

Ibutilide

Digoxin is intestinal () mediated

P-gp

Verapamil () digoxin drug levels and rifampin () digoxin drug levels.

Increases

Decreases

Chlorothiazide vs polythiazide

Polythiazide: More potent, longer half-life than chlorothiazide due to its increase in lipophilicity

Furosemide bumetanide structure both have a benzene ring w what two functional groups?

-COOH

-SO2NH

T/F: Furosemide and bumetanide have a long DOA

F → short DOA

T/F: Triamterene and Amiloride are both strong organic acids

F —> weak organic bases

What are Triamterene and Amiloride’s structures?

Triamterene (Pteridine)

Amiloride (Aminopyrazine)

T/F: Amiloride has a greater elimination half-life than triamterene

T

What is the metabolism of Amiloride and Triamterene?

Amiloride: Mostly excreted unchanged (renal)

Triamterene: Met. to major metabolites and are active as diuretics

Aldosterone antagonists (spironolactone, eplerenone) bind to ()

Mineralocorticoid receptor

Eplerenone has an () functional group and has a (greater/lower) affinity for MR than spironolactone

Eplerenone has an epoxy functional group and has a lower affinity for MR than spironolactone

T/F: propranolol is hydrophilic

F → lipophilic

Esmolol is a made of this structure ()

Aryloxypropanolamine

T/F: B1-selective antagonists atenolol and esmolol are short acting

T