Calcium Channel Inhibitors

• Calcium channel inhibitors, also known as calcium antagonists, block the transmembrane transfer of calcium in cardiac and vascular muscle cells

Calcium Channel Classifications

• Voltage-dependent calcium channels (VOC or POC) open when the membrane depolarizes
• VOCs are also called slow calcium channels due to their activation and inactivation kinetics
• Receptor-operated channels (ROC) open when agonists occupy specific membrane sites
• ROCs allow calcium ions to enter the cytoplasm, such as calcium channels associated with α2 adrenergic receptors
• Leak channels lack a gate mechanism, remaining continuously open and causing a small, constant influx of calcium into the cell

Calcium Channel Inhibitors

• Acting directly on voltage-dependent channels, they bind specifically to the channel and block it
• Inhibition causes vasodilation and reduces response to contractile stimuli
• Used to treat hypertension, angina, and myocardial infarction

Chemical Classification of Calcium Channel Inhibitors (ICA)

• Phenylalkylamines: Verapamil
• Dihydropyridines: Nifedipine
• Benzothiazepines: Diltiazem
• Other

Pharmacological Classification

• Vasoselective calcium antagonists: 1-4 dihydropyridines
• Mixed calcium antagonists: Benzothiazepines
• CardiodePressant calcium antagonists: Phenylalkylamines

Therapeutic Products: 1,4-Dihydropyridines

• General chemical structure includes R1, R2, R3, X, and Y substituents
• Nifedipine, Nicardipine, and Amlodipine are examples with varying substituents

Synthesis of 1,4-Dihydropyridines

• Synthesis begins with a base (ammonia) extracting a proton from the α-carbon of an alkyl acetylacetate
• This forms a carbanion that attacks electrophilically
• The carbanion adds nucleophilically to an aldehyde, forming an aldol
• Dehydration then generates an α,β-ethylenic ketone
• A second mole of alkyl acetylacetate reacts with ammonia to form a carbanion, which performs a Michael addition
• The reaction concludes with nucleophilic addition of ammonia to carbonyl, followed by dehydration to create 1,4-dihydropyridines

Structure-Activity Relationship for 1,4-Dihydropyridines

• The dihydropyridine cycle is essential, with the -NH- group playing a critical role
• Small alkyl substitutions optimize activity, allowing for replacements such as -NH2, -CN, or -CHO
• Bulky and electron-attracting ortho substituents enhance biological activity

Essential Groups for Activity

• Phenyl at position 4 of pyridine: Hetero-atomic cycles retain activity but increase toxicity. Cycloalkanes or alkyl groups reduce activity
• Phenyl substitution: Size, position, and electronic effects matter: Ortho or meta substitutions are more active than para or non-substituted ones
• 1-4 dihydropyridine cycle: Essential; piperidine or pyridine replacements abolish or diminish activity. Substitution on nitrogen at position 1 also has the same effect
• Esters at positions 3 and 5: Optimize activity; electron-attracting groups decrease antagonistic activity or cause agonistic activity

Phenylalkyl Amine

• Verapamil is an example
• Optimal tertiary amine enhances activity
• Bulky substituents decrease activity
• Aromatic cycles A and B are essential
• Isopropyl and cyano groups: Their substitution reduces activity
• S enantiomer is more active on calcium channels than the R enantiomer

Benzothiazepine

• Diltiazem is an example
• Key modifications affecting pharmacology on the benzene ring at carbon 2 of the heptacycle
• Methoxy replacement reduces activity, except for methyl, which maintains biological response

Mechanism of Action

• Calcium antagonists reduce intracellular calcium, promoting muscle fiber relaxation, especially in vascular smooth muscles
• Calcium antagonists inhibit calcium transport through calcium channels, calcium, release from intracellular stores, and calcium binding to calmodulin

Dihydropyridines Mechanism

• Primarily bind to L-type calcium channels in the inactivated state (mode 1)
• This induces an allosteric modification of the pore, preventing calcium entry and, subsequently, contraction
• Characterized by brief openings and prolonged closures

Verapamil and Diltiazem Mechanism

• Phenylalkylamine binding to intracellular sites interferes with ion movement
• Verapamil and Diltiazem bind better when the channel is activated (mode 2)
• Characterized by long openings and brief closings

Indications for Calcium Channel Inhibitors

• Hypertension (HTA)
• Arrhythmias
• Angina
• Raynaud's syndrome

Side Effects

• Dihydropyridines: Facial flushing, headaches, leg edema, hypotension, and moderate tachycardia
• Diltiazem: Leg edema and sinus bradycardia
• Verapamil: Peripheral edema, bradycardia, hypotension, constipation, and gastralgia

Contraindications

• Dihydropyridines: Allergy, pregnancy, and breastfeeding
• Diltiazem: Allergy to the product
• Verapamil: Allergy, pregnancy, breastfeeding, uncompensated heart failure, atrial fibrillation, and acute phase of myocardial infarction