Calciunnnnnnnnnnnnm Channel Blocker.pptx

Calciunnnnnnnnnnnnm Channel Blocker.pptx

• 1.
  Calcium Channel Blocker MODERATOR-Dr. Pinu Ranawat PRESENTER- Dr.Anjul Kumar Singh
• 2.
  Introduction • Calcium channelblockers (also known as calcium entry blockers and calcium antagonists) are a diverse group of structurally unrelated compounds that selectively interfere with inward calcium ion movement across myocardial and vascular smooth muscle cells. • Calcium ions play a key role in electrical excitation of cardiac cells and vascular smooth muscle cells.
• 3.
  Calcium channel • Voltage-gatedcalcium channels (VGCCs) are ion pores in the plasma membrane of electrically excitable cells. • They open in response to membrane depolarization and allow calcium influx from extracellular space. • Resulting increase in the intracellular free calcium concentration triggers or modulates a variety of physiological processes (such as contraction, secretion, neurotransmission, and gene expression). L-type of calcium channel
• 4.
  Types of CalciumChannel TYPE SUBTYPE LOCATION L Type (Long lasting) Cav1.1 a1 skeletal dihydropyridine receptor Cav1.2 a1 cardiovascular L-type channel Cav1.3 a1 neuroendocrine L-type channel Cav1.4 a1 retinal L-type channel T Type (Transient) nervous tissue, heart, kidney, smooth muscle, sperm, and many endocrine organs N Type (Neuronal) widely distributed in various region of the brain
• 5.
  Muscle contraction Cross-bridges withactin Activates Myosin Calcium calmodulin complex Intracellular Ca combines with Calmodulin Neural impulse Initiates an action potential Activates voltage gated channels Calcium ion influx Excitation Contraction Coupling
• 6.
  Excitation Contraction Coupling
• 7.
  Mechanism of Action •CCB bind to receptors on voltage-gated calcium ion channels resulting in maintenance of this channel in an inactive state. • As a result, calcium influx is decreased and there is reduction in intracellular calcium. • Calcium influx through L-type channels is responsible for phase 2 of the action potential, which is important in excitation-contraction coupling in cardiac and vascular smooth muscle and depolarization in SA and AV Nodel tissue.
• 8.
  Mechanism of Action
• 9.
  Differential effects ofdifferent CCBs on CV cells AV SN AV SN Potential reflex increase in HR, myocardial contractility and O2 demand Coronary VD Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for cardiac tissue and vasculature Heart rate moderating Peripheral and coronary vasodilation Reduced inotropism Peripheral vasodilation
• 10.
  Classification of CCBs
• 11.
  Phenylalkylamine-Verapamil • Synthetic derivativeof papaverine • The dextroisomer of verapamil is acts on fast sodium channels, accounting for the local anesthetic effects of verapamil (1.6 times as potent as procaine). • The levoisomer of verapamil is specific for slow calcium channels. • Metabolized by N-demethylation to norverapamil (less active).
• 12.
  Pharmacokinetics • Drug ismetabolized quickly and, as a result, has low bioavailability. • Liver is the main site of first-pass metabolism, forming several products. • The preferential metabolic step involves N-dealkylation, followed by O- demethylation, and subsequent conjugation of the product before elimination. • The metabolites have no significant biological activity. • Verapamil has an elimination half-life of 3-7 hours.
• 13.
  Phenylalkylamine….Verapamil Clinical uses Action Supraventriculartachydysrhythmias atrioventricular node Vasospastic angina pectoris mild vasodilating effects Essential hypertension mild vasodilating effects Hypertrophic cardiomyopathy negative inotropic effect maternal and fetal tachydysrhythmias atrioventricular node premature labour Uterine relaxant
• 14.
  CONTRA-INDICATIONS • Cardiogenic shock. •Severe bradycardia. • Sinus node dysfunction, or • Atrioventricular nodal block • severe left ventricular dysfunction. • Uncompensated heart failure. • Hypotension (systolic pressure <90 mm Hg),
• 15.
  • High lipid:waterpartition coefficient (lipophilic). • Have good oral absorption but lower bioavailability (50-65%) due to first-pass metabolism • 90-95% of the drug is bound to plasma proteins. Dihydropyrimidines…. N H NO2 C O O CH3 C O O H3C H CH3 Nifedipine (ProcardiaR ) N H C O O C O O H3C H Cl C2H5 CH2 O (CH2)2-NH2 Amlodipine (NorvascR ) N H NO2 C O O C O O H3C H CH3 (CH2)2-N CH3 CH2 Nicardipine (CardeneR ) N H C O O C O O H3C H CH3 O N N CH3 CH CH3 H3C Isradipine (DynacircR )
• 16.
  • Dihydropyridines areexcellent antihypertensive agents. • Potent arterial dilator with few venodilating effects. • Reflex activation of the sympathetic nervous system may increase HR. • Antianginal effects result from reduced myocardial oxygen requirements secondary to the afterload-reducing effect and to coronary vascular dilation resulting in improved myocardial oxygen delivery. • Can aggravate ischemic heart disease due to increased myocardial work. Dihydropyrimidines…
• 17.
  Nifedipine • Dihydropyridine derivativewith greater coronary and peripheral arterial vasodilator properties than verapamil. • There is minimal effect on venous capacitance vessels. • Unlike verapamil, nifedipine has little or no direct depressant effect on SA or AV node activity.
• 18.
  Nifedipine • Dose: • Oral-10-30 mg every 8 hrs • I.V.-5-15 μg/kg • Indications: • Chronic stable angina, • Prinzmetal’s angina. • Contraindications: • Nifedipine may produce excessive myocardial depression, especially in patients with preexisting left ventricular dysfunction or concomitant therapy with a β-adrenergic antagonist drug. • Aortic stenosis may also exaggerate cardiac depressant effects of nifedipine.
• 19.
  •Side effects: •Peripheral edema(venous congestion), •Hypotension, •Flushing, •Dizziness, •Headache, •Nausea, •Increased micturition frequency, •Skeletal muscle weakness •Paraesthesia
• 20.
  Amlodipine • It isa third generation 1,4-dihyropyridine derivative of the prototypical molecule nifedipine. • Only oral administration (5-10 mg) • Elimination halftime is 30 to 40 hours, and about 90% of the drug undergoes hepatic metabolism to inactive products. • Have minimal detrimental effects on myocardial contractility and provides anti-ischemic effects comparable to β-blockers in patients with acute coronary syndrome. • Combination of amlodipine and β-blockers may be more effective in the treatment of myocardial ischemia than either drug alone.
• 21.
  Nicardipine • Lacks effectson the SA node and AV node and has minimal myocardial depressant effects. • Has the greatest vasodilating effects of all the calcium entry blockers, with vasodilation being particularly prominent in the coronary arteries. • Available in IV and oral preparations. • The side effects of nicardipine are similar to nifedipine. • Uses- • As tocolytic drug. • 40 μg/kg IV administered immediately before performing electroconvulsive therapy, is effective in blunting acute hemodynamic responses.
• 22.
  Clevidipine • Third-generation dihydropyridine •Extremely lipophilic and ultrashort acting. • It is U.S. F.D.A approved for the treatment of acute, severe hypertension and is only available in an IV form. • Cleared by plasma esterases with a metabolism half-life of approximately 1 minute. • Dosing starts at 1 to 2 mg per hour and is doubled every 90 seconds until blood pressure approaches goal.
• 23.
  • Side effectsinclude hypotension and tachycardia • Contraindicated in • Hyperlipidemic states, • Acute or chronic pancreatitis, and • Heart failure with reduced ejection fraction as higher dose infusions have been associated with a negative inotropic effect that could precipitate acute decompensation
• 24.
  Nimodipine • Highly lipid-solubleanalogue of nifedipine. • Lipid solubility facilitates its entrance into the CNS, where it blocks the influx of extracellular calcium ions necessary for contraction of large cerebral arteries. • Clinical Uses - Useful in preventing or attenuating cerebral vasospasm that often accompanies subarachnoid hemorrhage. • 0.7 mg/kg orally as an initial dose followed by 0.35 mg/kg every 4 hours for 21 days for SAH. • Nimodipine also has been evaluated for cerebral protection after global ischemia, as associated with cardiac arrest.
• 25.
  Diltiazem hydrochloride • Benzothiazepinecalcium-channel blocker. • Exerts minimal cardiodepressant effects • Effects on the SA and AV nodes and its vasodilating properties appear to be intermediate between those of verapamil and the dihydropyridines. • Diltiazem have two additional effects - Act on sodium-potasium pump. - Inhibit calcium-calmodulin binding • Diltiazem attenuates baroreflex increases in HR secondary to NTG and decreases in HR secondary to phenylephrine.
• 26.
  •Uses • First-line medicationfor the treatment of supraventricular tachydysrhythmias • Essential hypertension • Angina Pectoris •Doses • Available as an oral capsule and can also be administered IV, especially for the management of angina pectoris. • Recommended IV dose is 0.25 to 0.35 mg/kg over 2 minutes and is repeated in 15 minutes, if needed. • Unlikely to interact with beta-adrenergic blocking agents.
• 27.
  Pharmacokinetics • Oral absorptionis excellent with an onset of action in 15 minutes and a peak effect in about 30 minutes • 70% to 80% bound to proteins and is excreted as inactive metabolites principally in bile (about 60%) and, to a lesser extent, in urine (about 35%). • Active metabolites include desacetyl diltiazem and desmethyl diltiazem. • Elimination half-time for the parent drug is 4 to 6 hours
• 28.
  Diltiazem hydrochloride Side Effects: CNS:Headache, fatigue, dizziness, asthenia, drowsiness, nervousness, insomnia, confusion, tremor, gait abnormality. CV: Edema, arrhythmias, angina, second- or third-degree AV block, bradycardia. CHF: flushing, hypotension, syncope, palpitations. GI: Nausea, constipation, anorexia, vomiting, diarrhoea, impaired taste, weight increase. Skin: Rash.
• 31.
  Drug Interaction Drug Interaction Digoxinplasma concentration of digoxin Beta-arenergic antagonist Enhanced Negative inotrope and chronotrope effects Beta-adrenergic agonists Counter the effects of CCBs H-2 antagonists plasma concentrations of CCBs diazepam, propanolol unbound portion of the verapamil Cyclosporine cyclosporine metabolism Carbamazepine carbamazepine metabolism, calcium channel blocker metabolism Cyclosporine cyclosporine metabolism Phenytoin, Rifampin, Barbiturates Metabolism of CCBs. Potassium containing fluid hyperkalemia Local anesthetics Risk of toxicity of both
• 32.
  THANK YOU