RX 412 E3: Chemistry of Calcium Channel Blockers

What type of drug is this?

1,4-DHP

What type of drug is this?

Phenylalkylamine

What type of drug is this?

Benzothiazepine

What combination of 1,4-DHP, Phenylalkylamine, and Benzothiazepine can you give that won’t inhibit each other’s action?

Benzothiazepine and 1,4-DHPs enhance each other’s activity

What is 1,4-DHPs impact on Peripheral vasodilation?

Increase

What are verapamil and diltiazem’s impact on Peripheral vasodilation?

Increase

What is 1,4-DHPs impact on blood pressure?

Decrease

What are verapamil and diltiazem’s impact on blood pressure?

Decrease

What is 1,4-DHPs impact on Heart rate?

Increase

What are verapamil and diltiazem’s impact on Heart rate?

Decrease or no effect

What is 1,4-DHPs impact of AV node conduction?

No effect

What verapamil and diltiazem’s impact of AV node conduction?

Decrease

What is 1,4-DHPs impact of contractility?

No effect or moderate increase

What are verapamil and diltiazem’s impact on contractility?

Decrease

What are the uses of this drug?

Hypertension and severe chest pain (Angina)

What is the MOA of this drug?

Stabilize inactivated state of L-type calcium channels

Which tissues does this drug effect more?

Tissues with depolarized membranes (Smooth muscles)

What is the result of taking this drug?

Reduced vasculature resistance and blood pressure

What is the impact of activity when substituting something para on the phenyl group of this drug?

Para-substituents on 1,4-DHPs reduce activity

What is the impact of substituting something meta or ortho in the phenyl group of this drug?

Peak activity

What group on the main ring is optimal for activity? Why?

C3 and C5 esters. Add chirality

What would happen if one of the esters were longer than the other in this drug?

Selectively target different blood vessels

What allows this drug to be formulated as IV?

Availability of the nitrogen on the left side

What is true of this molecules onset of action?

Faster than the others which make it best for hypertensive crisis

What is true about this molecule given it’s substituted group on C5?

It has higher lipophilicity so it crosses the BBB better and can be used for cerebral vasospasms

What happens when you substitute R5?

Increases potency and duration of action by reducing metabolism

What type of metabolism does this drug go through?

Heavy first pass

Why would a higher LogP have worse bioavailability in DHPs when that is not normally the case?

Bulky DHPs are great substrates for CYP enzymes

What is unique about this molecule?

Has active metabolites

What is unique about this molecule?

It is a soft drug

What class of drug is this?

Phenylalkylamine

What is this drug used to treat?

Hypertension

Angina

Arrhythmias

What three things do phenylalkylamines have a potent effect on?

Heart rate

AV node conduction

Heart contractility

What 2 things is verapamil specially used for that other phenylalkylamines aren’t?

supraventrucular tachycardia (Rapid and regular)

Atrial fibrillation (Irregular)

What is the MOA of this drug?

Binds to open and inactivated channels

What type of tissues does this drug have a higher affinity for?

Tissues with higher electrical activity

What is the result of blocking calcium channels in cardiac muscle?

Lower heart rate

Slower AV conduction

Reduced myocardial oxygen demand

What about this drug makes it available for IV formulation?

High pKa of its amine group

What is the off-label use for this drug?

Migraine and cluster headache prevention

Why does this drug have such a high half-life?

It has an active metabolite and it inhibits it’s own metabolism (CYP3A4) as well as P-glycoprotein

What is this drug used for?

Hypertension

Angina

Arrhythmias

Atrial fibrillation

When is this drug preferred in a patient?

Needs treatment of HPN and cardiac arrest because it works on both smooth muscle and cardiac muscle

Why does this drug have such a long half-life?

It is metabolized into 3 different active metabolites