Calcium channel blockers and nitrates

L type vg channels

Long lasting; importnat in cardiac and vascular SM

T-type vg channels

Found in neurons and pacemaker cells

General MOA for CCB’s

Inhibit Ca2+ influx through L-type CCB’s, antagonising Ca2+ movement across cell membranes

Effects of CCB’s

• Vasodilation of vascular (arteriole) SM

• -ve inotropic action (reduced force)

• -ve chronotropic action (reduced rate)

• -ve dromotropic action (reduces conduction velocity into ventricles)

Main therapeutic indications for CCB’s

• Hypertension: dihydropyridines

• Arrhythmias: diltazem

• Angina: verapamil and diltazem

Amlodipine + MOA

Dihydropyridine drug

MOA: binds to and inhibits L-type and T-type channels

Effects of amlodipine

Vasodilation of arterial smooth muscle decreasing TPR (afterload)

How is amlodipine vasoselective for arterial SM?

Binds to and stabilises L-type channels while in inactivated state, which mostly exists in arterial SM

Contra-indications of amlodipine

Shouldn’t be used for angina as it can increase myocardial O2 demand

Pharmacokinetics of almodipine

• Oral administration

• Bioavailability: 64% (completely absorbed from GI tract)

• Slow onset of action

• Peak plasma levels: 6-12 hours

• Achieves SSPC in 7 days

• Metabolised by CYP3A4

• once daily

Verapamil + MOA

Phenylalkylamine

MOA: binds to open LTCC binding domain and interferes w Ca2+ binding. This promotes inactive channel conformation ad slows recovery of inactvation, preventing Ca2+ from entering

Effects of verapamil

• Channel inhibition at higher HR’s

• Decreases cardiac contractility

• Vasodilator for arterial portion of peripheral vasculature

Indications for verapamil

• Angina

• Hypertension

Contra-indications of verapamil

Avoid in heart failure and use w b-blockers

Pharmacokinetics of verapamil

• Rapid and near complete oral absorption

• IV administration

• CYP3A4 metabolism

ADR’s of CCB’s

• Extension of the drug on vascular SM causing facial flushing and constipation

• Hypotension

• Bradycardia

• AV block

• Heart failure

Diltiazem + MOA

Benzothiazepine

MOA: inhibits Ca2+ influx during depolarisation primarily on cardiac and vascular smooth muscle

Contra-indications of diltizaem

Should not be used for patients on b blockers

Indications for diltiazem

• Anti-arrythmics (AF)

• Angina

• To reverse coronary vasospasm

Pharmacokinetics of diltiazem

• Highly absorbed (90%)

• Extensive 1st pass metabolism

• Interacts w drugs affecting CYP3A4

• CYP3A4 inhibitor

• Metabolised by CYP3A4

Erythromcyin

Drug which inhibits CYP3A4 thus potentiating dilitazem

Rifampicin, carbamazepine

Drugs which induce CYP3A4 thus causing loss of effect in diltiazem

Effects of NO on vascular smooth muscle

• Vasodilation

• Reduce platelet aggregation

• Anti-inflammatory

Prcoess of NO synthesis in endthelial cells

1. Ligand (Ach, bradykinin) bidns to lg Ca2+ vascular endothelial receptor

2. Ca2+ influx forms Ca-calmodulin from calmodulin

3. Ca-calmodulin activates eNOS, which converts L-arginine to citrilline and NO

eNOS

endothelial nitric oxide synthase; produces NO from L-arginine

Process of NO-induced vasodilation

1. NO binds to vascular smooth muscle and increases guanylate cyclase activity (cGMP)

2. cGMP activates cGMP-dependent protein kinase

3. Protein kinase promotes SERCA uptake of Ca2+ promoting smooth mucle relaxation

4. cGMP broken down by phosphodiesterase 5 (PDE5)

Funtion of nitrodilators

Mimic vasodilatory effects of endogenous NO by released NO either enymatically or spontaneously

Primary actions of nitrodilators

• Reduce venous P and preload by reducing diastolic LV wall stress and cardiac work

• Systemic arterial dilation (reduces afterload)

Indications for GTN

Acute angina (fast-acting)

Indications for isosorbide mononitrate or dinitrate

Long-term prophylaxis and management of coronary artery disease

Therapaurtic indications for nitrodilators

• Symptomatic relief of angina and MI

• Reverse vasospasm in Prinzmetal’s angina

• acute/ severe chronic heart failure

• Oedema

• Antiplatelet effect

• Hypertensive emergencies

ADR’s of nitrodilators

Dose-related effects (flushing, headache, reflex tachycardia, palpitations, hypotension, hypoxia, methemoglobinemia, skin lesions)

Drug interactions with nitrodiltors

• Alcohol

• Other vasodilators or hypertensives

• Phosphodiesterase inhibitors e.g. viagra