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Calcium Channel Blocking Drugs

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  1. Calcium Channel Blocking Drugs

  2. 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

  3. 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

  4. Canali del calcio: • VOC (Voltage operated channels) • ROC (Receptor operated channels • SMOC (Second Messanger operated channels)

  5. 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

  6. 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

  7. Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?

  8. N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ postsynaptic cell

  9. 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

  10. Ca2+ L-Type (graded, Ca2+ dependent contraction) Vascular smooth muscle relies on Ca2+ influx through L-type Ca2+ channels for contraction

  11. 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

  12. Differential states of L-type calcium channel active resting inactive

  13. 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

  14. Widespread use of CCBs • Angina pectoris • Hypertension • Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation • - Paroxysmal SVT

  15. Calcium Channel BlockersMechanisms of Action

  16. Calcium Channel BlockersMechanisms of Action

  17. 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

  18. Additional use of CCBs • Nimodipine and cerebral hemorrhage • Hemicranias (?) • Multi-drug resistance (MDR)

  19. 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

  20. 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

  21. 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

  22. Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + 0 + AV conduction defects ++ 0 ++ Severe cardiac failure ++ + + Contradications for CCBs

  23. Polialcoli esterificati con gli acidi nitrico e nitroso Glutatione S-transferasi Glutatione nitrato organico reduttasi Meccanismo d’azione dei nitroderivati

  24. 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

  25. Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Triad SR T Tubules of SR Skeletal muscle relies on intracellular Ca2+ for contraction

  26. Calcium Channel BlockersSide Effects • Palpitations • Headache • Ankle edema • Gingival hyperplasia

  27. CCBs - Monitoring • heart rate • blood pressure • anginal symptoms • signs of CHF • adverse effects