CALCIUM CHANNEL BLOCKERS

A. Chemical Structure

B. Duration of Action

CCB is classified based on?

Inhibit L-type (located in the heart and blood vessels) calcium channels; Ca influx ○

• In the brain, P, Q, and T type

• In the vessels and heart, L type

Inhibit the entry of calcium ions (important in muscle contraction) into cardiac and smooth muscles cell, capable to reduce TPR

It can also cause arteriolar vasodilation

Calcium channel blocker MOA

P,Q,T type

In the brain type wave

L type

In the vessel and heart type of wave

1. Opening of calcium channels resulting to the influx of calcium ions

2. Formation of Calcium-Calmodulin Complex

3. The complex will activate Myosin Light Chain Kinase (kinase=transfer of phosphates)

4. The myosin will now have a phosphate (Myosin LC PO4)

5. The Myosin LC PO4 will interact with the actin

6. Contraction

• Heart (cardiac contractions)

• Vessels (vasoconstriction)

Inhibition of this mechanism will stop the influx of calcium ions leading to no formation of phosphate and actin resulting to no contractions (decreased contractions=bradycardia(heart) vasodilatation(vessels))

Basic mechanism of CCB

Dihydropyridines

Nondihydropyridine

Based on structure types

Amlodipine (Norvasc)

Felodipine (Plendil)

Isradipine (DynaCirc)

Nicardipine (Cardene)

Nifedipine (Adalat, Procardia)

Nimodipine (Nimotop, Nymalize)

Nisoldipine (Sular)

Dihydropyridine examples of drug

Dihydropyridines

This structure commonly act on blood vessels (vasodilators)

Non-dihydropyridine

This structure is related to bradycardia and hypotension and Vasodilatation and blockade of calcium channels in the heart

Verapamil

Diltiazem

Type of Non-dihydropyridine

Diltiazem

benzothiazepine

Verapamil

phenylalkylamine

Verapamil

Result of attempts to synthesize more active analogs of papaverine, a vasodilator alkaloid found in the opium

Lacidipine

Lercanidipine

Amlodipine

A long acting CCB

Nifedipine (Adalat) GITS or Nifedipine gastrointestinal therapeutic system

Felodipine (Plendil ER or Extended release)

Verapamil SR or Sustained Release

A modified long acting CCB

The rest of the CCB

Short acting CCB

Heart failure

Induce vasodilation

CCB is not used in ____ beacause it will ___ that can worsen the disease

1. Management of hypertension(long acting)

2. Management of angina

3. Cerebral vasodilator (for cerebral aneurysm)

4. Dysrhythmias

5. Migraine headaches

6. Raynaud phenomenon

7. Subarachnoid hemorrhage

Use of CCB

Migraine headache

A paradoxical effect of CCB

Raynaud phenomenon

condition wherein there is too much constriction of vessels into the extremities

Pallor (no color) to cyanosis (bluish-purple hue) and cold clammy skin

Manifestation of Raynaud phenomenon

Highly protein bound

Large Volume of Distribution

Pharmacokinetics and Toxicokinetics

5.5 L/kg

Volume of Distribution of Verapamil

5.3 L/kg

Volume of Distribution of Diltiazem

0.8 L/kg

Volume of Distribution of Nifedipine

Reflex tachycardia (Give beta blocker)

• Compensatory response (contraction) of the heart to vasodilation resulting to vasoconstriction due to increase in cardiac output

• indirect when there is too much vasodilation

Peripheral edema (Give diuretic)

• Compensatory retention of water and salt

• indirect when there is too much vasodilation

Hypotension

• Caused by vasodilation

Adverse effect of Dihydropyridine

Bradycardia (Avoid beta blocker)

They can lower blood pressure to greater extent

Peripheral Edema (Give diuretic)

Expect hypotension

Adverse effect of Non-dihydropyridine

Dihydropyridine

This block the calcium levels causing vasodilation

Non-dihydropyridine

Blocks both the heart and veins

Constipation- common to Verapamil (papaverine derivative)

Gingival Hyperplasia

Hyperglycemia

• In pancreas, to release the insulin that requires action potential when calcium enters. Inhibition of calcium ions will inhibit action potential to release insulin causing hyperglycemia since insulin utilizes sugar in the blood.

Other adverse effect of CCB

Because these drugs also block the calcium channels in the heart decreasing-heart rate and Cardiac output

Why do non-dihydropyridines cause bradycardia?

As compensatory response due to decrease blood pressure due to vasodilation and blockade of calcium channels in the heart

Why do calcium channel-blockers cause Peripheral edema?