calcium channel blockers october 3, 2007 frank f. vincenzi

Download Calcium Channel Blockers October 3, 2007 Frank F. Vincenzi

Post on 24-Dec-2015

214 views

Category:

Documents

1 download

Embed Size (px)

TRANSCRIPT

  • Slide 1
  • Calcium Channel Blockers October 3, 2007 Frank F. Vincenzi
  • Slide 2
  • Ca signalling and Ca channel blockers: The fundamental information Ca 2+ Ca10 M 2+ -7-3 = = intracellular extracellular
  • Slide 3
  • Calcium The FIRST second messenger fundamental intracellular messenger for a wide variety of physiological responses in essentially all cell types (muscle tension, neurotransmitter/hormone release, production of inflammatory mediators) The LAST second messenger accumulation of intracellular Ca 2+ is a final common pathway in both apoptotic and necrotic cell death
  • Slide 4
  • Ca signalling: Two fundamental mechanisms Influx of Ca across the plasma membrane voltage-operated Ca channels (VOCs) receptor-operated Ca channels (ROCs) Internal release of Ca from intracellular stores (sarcoplasmic/endoplasmic reticulum) (SER) Ca-induced Ca release (trigger Ca) Inositol tris-phosphate( IP 3 ) induced Ca release Combinations of the above mechanisms
  • Slide 5
  • Intracellular Calcium Release Inositol tris-phosphate (IP 3 ) Present in almost all cells. IP 3 acts on sarcoplasmic/endoplasmic reticulum receptors (IP 3 Rs) IP 3 may sensitize Ca-induced Ca release Calcium-induced calcium release Mainly in striated muscle Ryanodine receptors (RyRs) RyR1 (predominantly in skeletal muscle) [Mutation associated with malignant hyperthermia] RyR2 (predominantly in cardiac muscle) RyR3 (predominantly in brain & non-muscle)
  • Slide 6
  • Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Na + Ca 2+ Ca 2+ Ca 2+ sarcolemma RyR SR Ca 2+ ATP Ca 2+ Agonist R O C R O C Receptor operated Ca channels mediate some agonist actions Ca 2+ Ca 2+ Ca 2+ Ca 2+
  • Slide 7
  • Ca signalling: Three examples Histamine on H-1 receptor activates phospholipase C and releases inositol trisphosphate (IP3), IP3 acts on SR/ER IP3 receptors causing Ca release (CHEMICAL) Norepinephrine on beta-1 receptors in heart couple to G protein and activate adenylyl cyclase; increase cAMP, activate protein kinase A (PKA), phophorylate a cytoplasmic domain of the Ca channel, increase Ca current; PKA also phosphorylates phospholamban, an SR protein and increases the activity of the SERCA pump; increase Ca storage and release (CHEMICAL/ELECTRICAL) Cell depolarization activates voltage operated Ca channels (VOCs) in the plasma membrane, promoting influx of Ca into the cell cytoplasm, may be amplified by Ca induced Ca release (ELECTRICAL)
  • Slide 8
  • Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Na + Ca 2+ Ca 2+ sarcolemma RyR SR Ca 2+ ATP Ca 2+ histamine IPR 3 IP3 PLC DAG Phospholipase C and inositol tris phosphate mediate some agonist actions by promoting intracellular Ca release Ca 2+
  • Slide 9
  • G AC 2+ Ca 2+ Ca 2+ Ca 2+ RyR 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Na + Ca 2+ sarcolemma Ca 2+ ATP Ca 2+ Beta-1 Receptor VOCVOC VOCVOC
  • Slide 10
  • norepinephrine G AC cAMP PKA P 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ RyR P 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Na + Ca 2+ sarcolemma Ca 2+ ATP Ca 2+ Beta-1 Receptor cAMP and protein kinase A mediate some of the positive inotropic effects of catecholamines by increasing Ca influx and intracellular Ca storage and release VOCVOC VOCVOC
  • Slide 11
  • Ca regulation of muscle tension: different in different types of muscle Reversible ionic binding of Ca to the Ca binding protein, troponin C (Ca/TNC disinhibits actin/myosin ATPase) skeletal myo (force varied by recruitment) cardiac myo (force varied by cellular regulation) Covalent modification of myosin light chain (Ca binds to the Ca binding protein, calmodulin CaM, CaM binds to MLCK, MLCK phosphorylates MLC, activates ATPase - tension) smooth myo (force varied by level of MLC phosphorylation)
  • Slide 12
  • The calcium cycle in HEART muscle Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Na + Ca 2+ Ca 2+ Ca 2+ Ca 2+ sarcolemma Ca channel, DHPR RyR SR Ca 2+ ATP Ca 2+ VOCVOC VOCVOC
  • Slide 13
  • The calcium cycle in SMOOTH muscle
  • Slide 14
  • The calcium cycle in SKELETAL muscle Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ sarcolemma Ca channel, DHPR RyR SR Ca 2+ Ca 2+ Ca 2+ Ca 2+ T-tubule
  • Slide 15
  • Ca regulation in muscle: variations on a few themes SR Ca 2+ actin myosin mitochondria VOC PMCA Na/Ca exchange Na/K pump Na + K + ROC
  • Slide 16
  • Muscle control: differential sensitivity to Ca channel blockers (CEBs)
  • Slide 17
  • Overview of Plasma Membrane Ca Channels Voltage operated channels (VOCs) L-type, N-type, T-type.etc. Receptor operated channels (ROCs) coupled to diverse receptors in the same cell Mechanically operated channels (MOCs) not widely appreciated (yet)
  • Slide 18
  • Voltage operated Ca Channels L-type (long, important in heart & smooth muscle) N-type (nerve, important in conduction & synaptic transmission) T-type (transient, heart & smooth muscle)
  • Slide 19
  • Calcium Channel Blockers Currently marketed Ca channel blockers all block L-type channels. Other terminology for these drugs: Calcium entry blockers (CEBs) Slow channel blockers Calcium antagonists (ugh!) (why NOT call them calcium antagonists?)
  • Slide 20
  • Chemical classifications of Ca channel blockers dihydropyridines e.g., nifedipine (Procardia) (have given the name to voltage operated Ca signaling proteins - the dihydropyridine receptor benzothiazepines e.g., diltiazem (Cardizem) phenylalkylamines e.g., verapamil (Isoptin, Calan)
  • Slide 21
  • In General Calcium Channel Blockers Are: Lipid soluble Rapidly absorbed Largely protein bound Of low bioavailability Metabolized by the liver
  • Slide 22
  • Calcium Channel Blockers: Site and Mechanism of Action L-type voltage operated channels (VOCs) and receptor operated channels (ROCs) Binding to Ca channel protein (slightly different site for each class): inhibits ionophoric activity of affected channels (all agents) delays recovery of the affected voltage operated channels (verapamil > diltiazem >> nifedipine)
  • Slide 23
  • Calcium Channel Blockers: Frequency Dependence Verapamil (and to some extent, diltiazem) selectively inhibits rapid cardiac rhythms by delaying recovery of calcium channels Dihydropyridines, such as nifedipine, have little or no effect on cardiac Ca channels in vivo
  • Slide 24
  • Calcium channel blockers: potencies for different tissues compared Smooth muscle dihydropyridines (e.g., nifedipine) >> verapamil ~ diltiazem Heart SA & AV nodes verapamil ~ diltiazem >> nifedipine myocardium verapamil > diltiazem >> nifedipine
  • Slide 25
  • Clinical Effects of Ca Channel Blockers Relax arteriolar smooth muscle, little or no venodilation Verapamil & diltiazem also depress SA and AV nodes and depress myocardial contractility to some extent. Dihydropyridines do not affect heart in vivo in normal doses Note: little or no effect on nervous system or skeletal muscle (no block of N-type Ca channels, and internal cycling of Ca, respectively)
  • Slide 26
  • Calcium Channel Blockers: Indications Angina (multiple mechanisms) Atrial arrhythmias (AV node conduction depends on Ca action potentials - some Ca channel blockers increase AV node refractory period) Hypertension (decrease vascular resistance) ( nifedipine for malignant hypertension) (sodium nitroprusside is a drug of choice here) (Raynauds syndrome?, asthma?, atherosclerosis?, reperfusion injury?)
  • Slide 27
  • nifedipine: indications Angina, variant angina Hypertension Off label aortic regurgitation, diabetic nephropathy, hiccups, hypertensive emergency/urgency, prophylaxis of migraine, premature labor (FDA-use-in-pregnancy C)
  • Slide 28
  • nifedipine: selected adverse reactions Hypotension Peripheral edema Flushing, headache
  • Slide 29
  • diltiazem: indications Angina, variant angina Atrial flutter, atrial fibrillation Paroxysmal supraventricular tachycardia Hypertension - slow release formulations only Off label Cardiomyopathy, diabetic nephropathy, proteinuria, prophylaxis of migraine
  • Slide 30
  • diltiazem: selected adverse reactions Depression of cardiac muscle AV nodal blockade Hypotension Peripheral edema Flushing, headache
  • Slide 31
  • verapamil: indications Angina, unstable angina, variant angina Atrial flutter, atrial fibrillation Paroxysmal atrial tachycardia (prevent and Tx) Hypertension Off label claudication, prophylaxis of migraine, mania
  • Slide 32
  • verapamil: selected adverse reactions Depression of cardiac muscle AV nodal blockade Hypotension Peripheral edema Flushing, headache Constipation
  • Slide 33
  • Psaty et al., (1995)* Use of short acting (emphasis added) Ca channel blockers, especially in high doses, and particularly when combined with diuretics, was associated with an increased risk of myocardial infarction. (None of the therapies monitored decreased MI risk significantly) Cochrane, different result with long acting CEBs *JAMA 274: 620-625, 1995
  • Slide 34
  • Scarlett OBrian Scarlett OBrian is a 38 year old female who was diagnosed with mild hypertension. She was given a prescription

Recommended

View more >