E2: CCB

Question 1

General Indication of CCBs

Answer 1

*HYPERTENSION
*Chronic stable angina, variant angina
*Dysrhythmias w/↑ HR: supraventricular tachycardia, atrial flutter, atrial fibrillation
*Subarachnoid hemorrhage (arterial spasms often present)
*Raynaud’s disease (severe vasospasm in the fingers set off by cold or overactivity, Red to blue to white (min to hrs))
*Migraines

Question 2

MOA of CCBs

Answer 2

CCB’s prevent Ca2+ from entering cardiac and vascular smooth muscle cells causing: ↓peripheral arterial vasodilation, ↓HR, coronary artery dilation
block alpha1 subunit (central pore of channel)

Question 3

Verapamil
Class
Pharmacologic effects
DI
ADR

Answer 3

phenylalkyamine
* ↑↑ peripheral vasodilation
* ↑↑ coronary vasodilation
* ↓↓ HR
* ↓↓ contractility
* ↓↓ SA node/AV node

DI:
*↑ plasma levels of digoxin and cyclosporine  ↓ dosing requirement
*metabolized by CYP3A4: inducers (ex rifampin)  ↓ plasma levels
inhibitors (ex erythromycin, cimetidine)  ↑ plasma levels
*Do not combine w/β blockers – negative HR and myocardial contractility
*P-glycoprotein- inhibits P-gp efflux pump ↑ antitumor agents cytotoxicity

ADR: constipation, edema, gingival hyperplasia

Question 4

Diltiazem-Cardizem (Tiazac, Dilacor)
Class
Pharmacologic effects
ADR
DI
CI

Answer 4

Benzothiazepines
* ↑↑ peripheral vasodilation
* ↑↑ coronary vasodilation
* ↓ HR
* ↓ contractility
* ↓ SA node/AV node
ADR
*CVS: Edema, AV block, bradycardia, hypotension, palpitations, flushing
*CNS: Headache, dizziness, pain, nervousness
*Others: skin rash, constipation, vomiting, weakness, rhinitis, pharyngitis, brochitis, cough, sinus congestion

DI
*↑ digoxin level; ↑ plasma levels of cyclosporine
*Metabolized by CYP3A4 inducers (ex rifampin)  ↓ plasma levels
inhibitors (ex erythromycin, cimetidine)  ↑ plasma levels

Contra-indications
*avoid in patients w/hypotension, sick sinus syndrome, AV block; acute MI & pulmonary congestion
Dihydropyridines

Question 5

nifedipine-Procardia, Nicardipine, Isradipine, Felodipine, Amlodipine
Class
Pharmacologic effects
ADR

Answer 5

Dihydropyridines
1st gen-nifedipine
3rd gen-amlodipine
* ↑↑↑ peripheral vasodilation
* ↑↑↑ coronary vasodilation
* -/↓ HR
* – contractility
* – SA node/AV node

CV: hypotension, flushing, peripheral/pedal edema
CNS: dizziness, lightheadedness, headache
GI: nausea, heartburn

Question 6

CCB Pharmacologic effect on Cardiac Muscle

Answer 6

• Block voltage-dependent L-type Ca2+ channels in the heart
   ↓ chronotropy and inotropy
   ↓ Ca2+ dependent Ca2+ release from the sarcoplasmic reticulum through Ryanodine receptors
• Cardiodepression  O¬2¬ demands ↓

Question 7

CCB Pharmacologic effect on Vascular Smooth Muscle

Answer 7

• Blood vessels: arterial vascular smooth muscle relaxation  arteriolar dilation
   Ca2+ dependent contraction blocked
   afterload reduced –> ↓ peripheral resistance –> ↓ BP

Question 8

CCB Pharmacologic effect as antiarrhythmic agents

Answer 8

• MOA: block slow inward Ca2+ channels in the heart
   Primary region affected: SA and AV nodes (phase 0 in pacemaker cells)
   inhibit Ca2+ influx ↓ phase 0  ↓ conduction velocity
   Block L-type VDCC  ↓ excitability SA node & ↓ AV node conduction – negative chronotropic effect
   ↓ effect of ventricular contractile cells (phase 2)

Question 9

SAR of dihydropyridines
C4
C3/C5
C2/C6
Para position
N1
ortho/meta positions

Answer 9

C4: substituted phenyl ring ↑ activity
C3/C5: nonidentical esters ↑ activity
C2/C6: larger substituents here can be tolerated by the 1,4 DHP receptor
Para position: MUST be unsubstituted
N1: MUST be unsubstituted
ortho/meta positions: substitution here ↑ activity, if bulky conformation will be locked so C4 aromatic is perpendicular to 1,4 DHP