Calcium Channel Blocking Drugs

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

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

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

The  1C subunit of the L-type Ca 2+ channel is the pore-forming subunit D N V N Domini Segmenti

 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

Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?

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

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+

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+

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

Differential states of L-type calcium channel restingactive inactive

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  mV 22  Diltiazem Verapamil 11  11 out  in 22  11 Nifedipine Cell membrane mV

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

Calcium Channel Blockers Mechanisms of Action

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

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

Agent Oral Absorption (%) Bioavail- Ability (%) Protein Bound (%) Elimination Half-Life (h) Verapamil> * Diltiazem> Nifedipine> Nicardipine >952-4 Isradipine > >958-9 Felodipine > Amlodipine > CCBs: Pharmacokinetics

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

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

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

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

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

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

Calcium Channel Blockers Side Effects PalpitationsHeadache Ankle edema Gingival hyperplasia

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