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Calcium Channel Blocking Drugs. Chemical Type. Chemical Names. Brand Names. Phenylalkylamines. verapamil. Calan, Calna SR, Isoptin SR, Verelan. Benzothiazepines. diltiazem. Cardizem CD, Dilacor XR. 1,4-Dihydropyridines. Nifedipine nicardipine isradipine felodipine amlodipine.
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Calcium Channel Blocking Drugs
Chemical Type Chemical Names Brand Names Phenylalkylamines verapamil Calan, Calna SR, Isoptin SR, Verelan Benzothiazepines diltiazem Cardizem CD, Dilacor XR 1,4-Dihydropyridines Nifedipine nicardipine isradipine felodipine amlodipine Adalat CC, Procardia XL Cardene DynaCirc Plendil Norvasc Three Classes of CCBs
Prima generazione Seconda generazione Terza generazione Phenylalkylamines Vi appartengono formulazioni a lento rilascio dei CCBs di prima generazione Altamente lipofile. Benedipina lacidipina, lecarnidipina Benzothiazepines 1,4-Dihydropyridines nicardipine isradipine felodipine amlodipine Three Classes of CCBs
Canali del calcio: • VOC (Voltage operated channels) • ROC (Receptor operated channels • SMOC (Second Messanger operated channels)
I II III IV Out In 6 IV III 5 5 IV III 6 II I The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit D Domini V N N Segmenti
CCBs – Mechanisms of Action • Increase the time that Ca2+ channels are closed/inactivated • Relaxation of the arterial smooth muscle but not much effect on venous smooth muscle • Significant reduction in afterload but not preload
Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?
N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ postsynaptic cell
Ca2+ Ca2+ L-Type L-Type Ca2+ Ca2+ Ca2+ Contractile Cells (atria, ventricle) Slow Response Cells (SA node, AV node) Cardiac cells rely on L-type Ca2+ channels for contraction and for the upstroke of the AP in slow response cells
Ca2+ L-Type (graded, Ca2+ dependent contraction) Vascular smooth muscle relies on Ca2+ influx through L-type Ca2+ channels for contraction
Peripheral vasodilation Differential effects of different CCBs on CV cells Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for cardiac tissue and vasculature Heart rate moderating Peripheral and coronary vasodilation SN AV Potential reflex increase in HR, myocardial contractility and O2 demand Coronary VD SN AV Reduced inotropism
Differential states of L-type calcium channel active resting inactive
The different binding sites of CCBs result in differing pharmacological effects Use-dependent binding (targets cardiac cells) out +20 2 mV 1 Cell membrane 1 -80 in Diltiazem Verapamil Voltage-dependent binding (targets smooth muscle) +20 out -30 2 Cell membrane 1 -80 1 mV in Nifedipine
Widespread use of CCBs • Angina pectoris • Hypertension • Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation • - Paroxysmal SVT
Effect Verapamil Diltiazem Nifedipine Peripheral vasodilatation Coronary vasodilatation Preload 0 0 0/ Afterload Contractility 0/ /* Heart rate 0/ /0 AV conduction 0 Hemodynamic Effects of CCBs
Additional use of CCBs • Nimodipine and cerebral hemorrhage • Hemicranias (?) • Multi-drug resistance (MDR)
Agent Oral Absorption (%) Protein Bound (%) Elimination Half-Life (h) Bioavail- Ability (%) Verapamil >90 10-35 83-92 2.8-6.3* Diltiazem >90 41-67 77-80 3.5-7 Nifedipine >90 45-86 92-98 1.9-5.8 Nicardipine -100 35 >95 2-4 Isradipine >90 15-24 >95 8-9 Felodipine -100 20 >99 11-16 Amlodipine >90 64-90 97-99 30-50 CCBs: Pharmacokinetics
Diltiazem Verapamil Dihydropyridines Overall 0-3% 10-14% 9-39% Hypotension ++ ++ +++ Headaches 0 + +++ Peripheral Edema ++ ++ +++ Constipation 0 ++ 0 CHF (Worsen) 0 + 0 AV block + ++ 0 Caution w/beta blockers + ++ 0 Comparative Adverse Effects
Agent Drug Pharmaco- kinetics effect Clinical effects Mechanism Verapamil Digoxin Clearance PC Digoxin tox. Verapamil Terfenedine CYP3A PC > QT Diltiazem Cyclosporin CYP3A PC Renal tox. Diltiazem Tacrolimus CYP3A CYP3A PC Renal tox. Verapamil ß-blockers PC Toxicity Nifedipine Riphampicin Clearance PC < CCBs effect Amlodipine Teophilline Clearance PC Toxicity CCBs: Pharmacokinetics interaction (CYP 3A and Glycoprotein-P inhibition
Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + 0 + AV conduction defects ++ 0 ++ Severe cardiac failure ++ + + Contradications for CCBs
Polialcoli esterificati con gli acidi nitrico e nitroso Glutatione S-transferasi Glutatione nitrato organico reduttasi Meccanismo d’azione dei nitroderivati
CCBs Act Selectively on Cardiovascular Tissues • Neurons rely on N-and P-type Ca2+ channels • Skeletal muscle relies primarily on [Ca]i • Cardiac muscle requires Ca2+ influx through L-type Ca2+ channels - contraction (fast response cells) - upstroke of AP (slow response cells) • Vascular smooth muscle requires Ca2+ influx through L-type Ca2+ channels for contraction
Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Triad SR T Tubules of SR Skeletal muscle relies on intracellular Ca2+ for contraction
Calcium Channel BlockersSide Effects • Palpitations • Headache • Ankle edema • Gingival hyperplasia
CCBs - Monitoring • heart rate • blood pressure • anginal symptoms • signs of CHF • adverse effects