Calcium Channel Blockers Flashcards
What does the vascular tone and contraction primarily rely on?
Availability of calcium from extracellular and intracellular sources.
What regulates influx of Ca2+?
Potential dependent Ca2+ channels
What happens in the vascular smooth muscle and in the heart muscle?
-In vascular smooth muscle, this corresponds to muscle contractions which lead to vasoconstriction and increase in blood pressure.
-In heart muscle, the effects are an increase in heart rate and a stronger
Are arterial or venous more sensitive to calcium channel blockers CCB?
Arterial smooth muscles.
Coronary and cerebral arterial vessels are more sensitive than other arterial beds.
So CCB are useful for hypertension, ischemic heart disease, and paroxysmal Supra-ventricular tachycardia.
3 chemical classifications of CCB?
1) 1,4 - dihydropyradines ( nifedipine)
2) Phenylalkylamines ( verapamil)
3) Benzothiazepines
Majority are 1,4 - DHPs
Different structural classes bind to distinct sites ( allosteric binding) on calcium ion channels.
Dihydropyridines
selective for ion channels in vascular smooth muscle so used for hypertension treatment
Dihydropyridine’s activity as CCB depends on
1- structures are hydrophobic meaning that they interact with hydrophobic binding sites
2- Nitrogen in DHP must be unsubstituted
3- Small hydrophobic alkyl groups are preferred in position 2 and 6
4- Ester groups are preferred at position 3 and 5
5- Aryl substituent at position 4 (ortho or meta position) but a substituent at para position is bad for activity
How does phenyl ring substitution affect compounds?
They are important for size and position rather than for electronic nature
How does ortho or meta substitutions affect compound?
They possess optimal activity to provide sufficient bulk to lock the confirmation (confirmational blocker) of the 1,4- DHP such that the C4 aromatic ring is perpendicular to 1,4- DHP ring. This perpendicular confirmation is essential for activity.
Dihydropyradine ring
-essential for activity
- it’s preferred confirmation is a flattened boat structure with aryl substituent in an axial position
- aromatic ring is perpendicular to DHP ring such that one of the ortho protons hangs in front of dihydropyridine ring.
-substituents on the aromatic ring points away from DHP
All calcium channel blockers (CCB) undergo extensive first pass metabolism and are substrates for the CYP3A4 isozyme except
Clevidipine.
It has ultrashort duration of action exerting it’s anti hypertensive actions within 2 to 4 minutes.
Phenylalkylamines (verapamil)
-contains a hydrophobic aromatic ring and an aliphatic tertiary amine
- it blocks the calcium ion channels by binding to an intracellular binding site. Structures have to cross cell membrane to reach binding site.
Tertiary amine of Phenylalkylamines
- Although it is mostly protonated at physiological pH, drug exits as the free base ( unionized) and so it can cross membrane.
- a quaternary amine causes a loss in activity
Verapamil
-a type of Phenylalkylamine
- treats hypertension by blocking calcium ion channels in vascular smooth muscle
-useful in treating arrhythmias by blocking calcium ion channels in cardiac muscle.
Benzodiazepines ( Diltiazem)
-treats hypertension and angina
-has two chiral centers ( 4 possible stereoisomers) while only 2S,3S isomer is active.
