Calcium Channel Blockers

What is the role of calcium in the cardiovascular system?

• electric signal conduction (AV + SA node, bundle of His)

• cardiac muscle contraction

What is the role of calcium in the blood vessels?

• smooth muscle contraction

  • vasoconstriction

  • increase in BP

Calcium enters through what type of channel?

L channels in the CV system

Explain the stepwise events of calcium entry into a single cell of the cardiac system?

Phase 0 = Na influx

Phase 1 = K+ efflux (hyperpolarization)

Slow Phase 2 = slow Ca2+ influx

• “plateau phase”

• end of phase → K+ efflux

Phase 3

• Ca can either:

  • triggers conduction systems OR

  • increase contraction of cardiac muscle

Phase 4 = Na/K ATPase pump

• Na and Ca efflux

• K+ influx

• return to resting MP

What 2 ions contribute to the electrical system completion by calcium?

Na and K

What is the resting membrane potential of a cardiac cell?

-80 mV

What are the 3 major cardiovascular conditions indicated for CCBs?

1. HTN (arteries)

2. angina (BVs in heart)

3. arrhythmia (cardiac muscle)

What are the 3 chemical nuclei that have properties to block CCs?

1. dihydropyridines (DHP)

2. arylalkylamines

3. benzothiazepines

Dihydropyridine acts exclusively on the ____ ____ 

blood vessels

What are the indications for dihydropyridines?

• angina

• HTN

What is the MOA of DHPs?

• do NOT have affinity to calcium channels in the heart

  • indirectly causes reflex tachycardia via the baroreceptor reflex

    • decrease in BP = increase in HR

What are the key features of 1,4-dihydropyridines?

• pyridine nucleus

  • 1 of the 3 double bonds is hydrogenated

  • 2 H’s are in 1,4 position

Nifedipine

• 1,4-dihydropyridine

• 2 alkyl chains at 2,6 position (methyls)

• 2 esters in 3,5 position

  • low bioavailability due to

    • lipophilicity (esters will be hydrolyzed easily, no polar groups)

    • high 1st pass metabolism

• phenyl ring in position 4

  • e withdrawing group at 2,3 position of phenyl

• N atom is completely nonbasic due to conjugation of lone pair

Nifedipine is only given orally due to what factors?

• cannot form a salt for injection

• suffers 1st pass metabolism

• low bioavailability

• metabolized by esterase enzymes in GIT, liver, and plasma

What are the different doses of nifdedipine?

• 5 mg

• 10 mg

• 20 mg

Nicardipine

• 1,4-dihydropyridine

• basic N on ester alkyl at position 3

• only given as injection (HCl salt) due to low bioavailability

Amlodipine 

• 1,4-dihydropyridine

• basic N in side chain at position 2

  • allows for formation of a salt with besylate → allows to be SLOWLY released → long acting product

Compare the besylate salt of amlodipine to the HCl salt of nicardipine.

• HCl salt → hygroscopic

• besylate salt → NOT hygroscopic

  • allows drug to be released SLOWLY as a long acting product dosed once daily

Where do benzothiazepines and arylalkylamines have highest affinity to calcium channels?

both blood vessels AND heart

Benzothiazepines and arylaklyklamines are used for what indications?

• arrhythmia

• HTN

• angina

What is the effect of benzothiazepines and arylalkylamines?

• (-) chronotropic effect

  • decrease in HR by directly inhibiting cardiac muscle contractions

All 3 nuclei are more selective to (veins/arteries) than (veins/arteries). They cause (arterial/venous) vasodilation and decreased (preload/afterload) in angina.

• arteries

• veins

• arterial

• afterload

What is the key feature of aryl-alkyl amines?

• aliphatic tertiary Nitrogen surrounded by carbon chains attached to aromatic rings

• least active class

Verapamil

• aryl-alkyl amine

• cyano group

• aliphatic tertiary amine

  • N demethylation on methyl → very low bioavailability

• 4 ether groups 

  • O demethylation → very low bioavailability

• no polar groups = increased lipophilicity

What are the dosage forms of verapamil?

• oral

• injection as HCl salt

Describe what happens when you take verapamil orally.

• there will be a high absorption rate due to its high lipophilic nature

• will also excessively undergo 1st pass metabolism (O/N-demethylation) → very low bioavailability

  • only 7% of oral dose reaches circulation intact

What are the key features of benzothiazepines?

thiazepine

• 7-membered ring

  • sulfur

  • nitrogen

• high absorption → very lipophilic

• high plasma protein binding (PPB) → very lipophilic

• low bioavailability due 1st pass metabolism → esters are quickly hydrolyzed

• identical properties to verapamil in:

  • HCl salt formulation and given IV

Diltiazem

• benzothiazepine

• ether group

  • O demethylation

• ester group

  • easily hydrolyzed by esterases = low bioavailability

• amide group

  • hydrolyzed by amidases → NH4 + COOH

• tertiary amine