2.2.3 CCB Classes and Indications

ADME of CCB

A- significant "first-pass effect"

D- high protein binding

M- CYP 3A4

E- half life varies

CCBs with short half-lives cause rapid change in BP, they can be associated with _____________

dizziness and flushing, and can also lead to reflex tachycardia

Long half-life or sustained release CCBs have less ________

reflex tachycardia, dizziness, and flushing

Non-Dihydropyridines (Non DHPs)

- Benzothiazepines (Diltiazem)

- Phenylalkylamines (Verapamil)

Dihydropyridines (DHPs)

Amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, nimodipine

Dihydropyridine moiety

Non-DHPs can directly affect:

- chronotropic (↓HR)

- inotropic (↓contractility)

- dromotropic (↓conduction velocity)

Non-DHP or DHP CCBs? Inhibit L-Type calcium channels in arterial smooth muscles promoting vasodilation and ↓TPR

Both CCBs

Non-DHP or DHP CCBs? Less potent vasodilators, but have more effect on CO

Non-DHPs

Non-DHP or DHP CCBs? More potent vasodilators, but have less effect on CO

DHPs

Effects on the Heart that are more prominent in Non-DHPs:

- suppression of cardiac contractility (negative ionotropic effect)

- suppression of automaticity (↓HR, negative chronotropic effect)

- suppression of conduction (negative dromotropic)

Effects on the Heart that are more prominent in DHPs:

Decreased TPR

Among calcium channel blockers, DHPs have ______, whereas non-DHPs have ________, with ______ showing the greatest depression of contractility.

- maximal vasodilation with minimal cardiac effects

- (verapamil > diltiazem) strong slowing of SA-node rate and AV-node conduction

- verapamil

DHPs (-dipine) Approved Indications

Angina (chest pain or discomfort caused by hypoxia of cardiac tissue)

DHPs are also not used as first line for______ or _____ due to lack of direct effects on L-type channels in cardiac tissue

supraventricular tachycardia or atrial fibrillation

Precautions with Non-DHPs (Vera, Diltia)

1. Advanced heart block

2. Severe aortic stenosis

3. cardiogenic shock

4. Avoid combining non-DHPs with BBs in patients with low HR

The best anti-anginal DHPs are more selective for coronary blood vessels, which include ________

- Amlodipine,

- nifedipine, nicardipine

Precautions with DHPs (-dipine)

1. Severe aortic stenosis

2. Cardiogenic shock

Other general/relative considerations for both DHPs and Non-DHPs

1. Avoid use in patients with renal failure

2. Avoid in patients with GERD bc CCBs enhance the symptoms

ADRs associated with Non-DHPS

• First Degree AV block

• Bradycardia

• Exacerbation of chronic heart failure or cardiac

• Constipation

• Nausea and vomiting, diarrhea, anorexia

• Flushing, headache, peripheral edema, dizziness

Which ADR is more common in Verapamil vs Diltiazem?

Constipation

Adverse Events associated with DHPs

• Peripheral edema

• Nausea and vomiting, diarrhea, anorexia

• Flushing, headache, dizziness

Avoid combining CCBs with:

1. Anasthetics

2. Amiodarone (anti-arrythmic)

3. Digoxin

4. Beta-Blockers

5. Prednisone

6. Use caution in combining with other drugs metabolized by CYP3A4

CCBs should not be given with ______ that could lead to an additive effect and cause _________

- other heart failure drugs

- hypotension

Avoid combining CCBs with CYP3A4 inhibitors, such as:

• Protease inhibitors

• Azole antifungals

• SSRIs

• Grapefruit juice

Avoid combining CCBs with CYP3A4 inducers, such as:

Rifampin (an antibiotic)

A patient with hypertension has a history of tachycardia (elevated HR). What might be the best CCB to prescribe?

a) Amlodipine

b) Nifedipine

c) Verapamil

d) Captopril

c) Verapamil

a non-DHP that lowers HR (negative chronotropy) and AV conduction (negative dromotropy) while reducing BP

Which statement best contrasts hemodynamic effects of CCB classes?

A. Non-DHPs primarily ↓TPR with minimal CO effect; DHPs mainly ↓CO

B. DHPs primarily ↓TPR with minimal CO effect; non-DHPs have stronger ↓CO effects

C. Both classes equally reduce CO with little effect on TPR

D. DHPs and non-DHPs have identical chronotropic effects

B. DHPs primarily ↓TPR with minimal CO effect; non-DHPs have stronger ↓CO effects.

Which combination poses the greatest risk of profound bradycardia/heart block?

A. Amlodipine + ACE inhibitor

B. Nifedipine ER + thiazide

C. Verapamil + β-blocker (in low HR)

D. Diltiazem + ARB

C. Verapamil + β-blocker (in low HR).

Non-DHPs depress SA/AV nodes; combining with β-blockers can worsen bradycardia/AV block.

Which adverse event is most characteristic of verapamil among CCBs?

A. Peripheral edema

B. Constipation

C. Cough

D. Hyperkalemia

B. Constipation

Non-DHPs reduce GI smooth-muscle motility; constipation is notably common with verapamil.

A patient with chronic stable angina and well-preserved LV function is started on a DHP for adjunct anti-anginal therapy. The expected anti-ischemic benefit is mainly due to:

A. Direct SA-node suppression

B. Coronary and systemic vasodilation reducing afterload

C. AV-node conduction slowing

D. Increased venous tone

B. Coronary and systemic vasodilation reducing afterload.

Certain DHPs (e.g., amlodipine, nifedipine, nicardipine) are effective adjuncts via vasodilation.

Which formulation strategy best minimizes dizziness/flushing and reflex tachycardia with CCBs?

A. Immediate-release products with short t½

B. Co-administration with loop diuretics

C. Extended-release or long t½ formulations

D. Delayed-release enteric coatings only

C. Extended-release or long t½ formulations.

Smoother plasma profiles reduce reflex effects.

A hospital adds ketoconazole to treat onychomycosis in a patient taking diltiazem. What is the key concern?

A. Reduced diltiazem efficacy via enzyme induction

B. Marked hypotension via CYP3A4 inhibition increasing diltiazem levels

C. QT prolongation from additive K⁺ channel block

D. Hyperkalemia from RAAS inhibition

B. Marked hypotension via CYP3A4 inhibition increasing diltiazem levels.

Azole antifungals inhibit CYP3A4.

Which adverse-event profile best matches non-DHPs?

A. Reflex tachycardia, flushing, edema; little nodal effect

B. Bradycardia, AV block, negative inotropy; constipation possible

C. Hyperglycemia and cough

D. Bronchospasm and hypokalemia

B. Bradycardia, AV block, negative inotropy; constipation possible

Which statement about general considerations is most accurate?

A. CCBs are renally cleared and unaffected by liver disease

B. CCBs increase lower esophageal sphincter tone and improve GERD

C. Many CCBs are extensively protein-bound and undergo first-pass metabolism

D. CCBs are preferred first-line for supraventricular tachycardia in all cases

C. Many CCBs are extensively protein-bound and undergo first-pass metabolism