1. Calcium Channel Blocking Drugs

2. Chemical TypeChemical NamesBrand Names PhenylalkylaminesverapamilCalan, Calna SR, Isoptin SR, Verelan BenzothiazepinesdiltiazemCardizem CD, Dilacor XR 1,4-DihydropyridinesNifedipine nicardipine isradipine felodipine amlodipine Adalat CC, Procardia XL Cardene DynaCirc Plendil Norvasc Three Classes of CCBs

3. Prima generazioneSeconda generazioneTerza generazione PhenylalkylaminesVi 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. The  1C subunit of the L-type Ca 2+ channel is the pore-forming subunit D N V N Domini Segmenti

7.  Increase the time that Ca 2+ 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 CCBs – Mechanisms of Action

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

9. N-type and P-type Ca 2+ channels mediate neurotransmitter release in neurons postsynaptic cell Ca 2+

10. Cardiac cells rely on L-type Ca 2+ channels for contraction and for the upstroke of the AP in slow response cells Contractile Cells (atria, ventricle) L-Type Ca 2 + Slow Response Cells (SA node, AV node) L-Type Ca 2+

11. Vascular smooth muscle relies on Ca 2+ influx through L-type Ca 2+ channels for contraction (graded, Ca 2+ dependent contraction) L-Type Ca 2+

12. Differential effects of different CCBs on CV cells AV SN AV SN Potential reflex increase in HR, myocardial contractility and O 2 demand Coronary VD Dihydropyridines: Selective vasodilatorsNon -dihydropyridines: equipotent for cardiac tissue and vasculature Heart rate moderating Peripheral and coronary vasodilation Reduced inotropism Peripheral vasodilation

13. Differential states of L-type calcium channel restingactive inactive

14. The different binding sites of CCBs result in differing pharmacological effects Voltage-dependent binding (targets smooth muscle) Use-dependent binding (targets cardiac cells) Cell membrane 11  out in  +20 -80 mV 22  Diltiazem Verapamil 11  11 out  in +20 -80 -30 22  11 Nifedipine Cell membrane mV

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

18. Calcium Channel Blockers Mechanisms of Action

20. EffectVerapamilDiltiazemNifedipine Peripheral vasodilatation  Coronary vasodilatation  Preload000/ Afterload   Contractility  0/ / */ * Heart rate 0/  /0 AV conduction  0 Hemodynamic Effects of CCBs

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

22. Agent Oral Absorption (%) Bioavail- Ability (%) Protein Bound (%) Elimination Half-Life (h) Verapamil>9010-3583-922.8-6.3* Diltiazem>9041-6777-803.5-7 Nifedipine>9045-8692-981.9-5.8 Nicardipine -100 35>952-4 Isradipine >90 15-24>958-9 Felodipine -100 20>9911-16 Amlodipine >90 64-9097-9930-50 CCBs: Pharmacokinetics

23. DiltiazemVerapamilDihydropyridines Overall0-3%10-14%9-39% Hypotension++ +++ Headaches0++++ Peripheral Edema ++ +++ Constipation0++0 CHF (Worsen)0+0 AV block+++0 Caution w/beta blockers +++0 Comparative Adverse Effects

24. AgentDrug Mechanism Pharmaco- kinetics effect Clinical effects Verapamil Digoxin  Clearance  PC Digoxin tox. VerapamilTerfenedine  CYP3A  PC > QT DiltiazemCyclosporin  CYP3A  PC Renal tox. Diltiazem Tacrolimus  CYP3A  PC Renal tox. Verapamilß-blockers  PC Toxicity Nifedipine Riphampicin  Clearance  PC < CCBs effect AmlodipineTeophilline  Clearance  PC Toxicity CCBs: Pharmacokinetics interaction (CYP 3A and Glycoprotein-P inhibition

25. ContraindicationVerapamilNifedipineDiltiazem Hypotension++++ Sinus bradycardia +0+ AV conduction defects ++0 Severe cardiac failure ++++ Contradications for CCBs

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

33. CCBs Act Selectively on Cardiovascular Tissues  Neurons rely on N-and P-type Ca 2+ channels  Skeletal muscle relies primarily on [Ca] i  Cardiac muscle requires Ca 2+ influx through L-type Ca 2+ channels - contraction (fast response cells) - upstroke of AP (slow response cells)  Vascular smooth muscle requires Ca 2+ influx through L-type Ca 2+ channels for contraction

34. Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Tubules of SR Triad T SR Skeletal muscle relies on intracellular Ca 2+ for contraction

35. Calcium Channel Blockers Side Effects PalpitationsHeadache Ankle edema Gingival hyperplasia

36.  heart rate  blood pressure  anginal symptoms  signs of CHF  adverse effects CCBs - Monitoring