Uploaded byDr. Amit Sharma
Final calcium
This document discusses calcium channels and their roles in various physiological systems. It begins with a brief history and overview of calcium channel functions in signal transduction, exocytosis, the muscular, vascular, nervous and cardiac systems. It then examines specific calcium channel roles and related drugs in more depth for these different systems, including details on calcium homeostasis. Recent FDA-approved drugs targeting calcium channels or related pathways are listed at the end.
Final calcium
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- 2. History Functions:-- 1.Signal transduction 2. Calcium mediated exocytosis 3. Muscular system, vascular system, nervous system and heart 4. Calcium homeostasis Recent advances Take home message
- 3. Principal founders inthe field of voltage-gated calcium channels :- A. Sir Bernard Katz B. Susumu Hagiwara C. Harald Reuter
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- 5. G protein coupledreceptors
- 6. Adenylyl cyclase: cAMP Activationof G-protein coupled receptors through ligand (primary messenger) Adenylyl cyclase cAMP (secondary messenger) opening of calcium channels activation of protein kinase A Protein phosphorylation
- 7. Adenylyl cyclase: cAMP •Adrenergic- β • Histamine-H2 • Dopamine-D1 • Prostacyclin-IP • Adrenergic- α2 • Dopamine-D2 • 5-HT1 • GABAB • Opioid- μ, δ • Angiotensin-AT1 • Prostaglandin-EP3 • Somatostatin • Adenosine-A1
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- 9. Phospholipase C :IP3-DAG • Adrenergic- α1 • Histamine-H1 • Muscarinic-M1,M3 • 5-HT2 • Vasopressin-Oxytocin • Angiotensin-AT1 • Prostaglandin-FP, EP3 • Leukotriene • EndothelinA , endothelinB
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- 12. Ca++ triggers bindingof SNARE COMPLEX (Soluble N- ethylmaleimide-sensitive factor Attachment Protein REceptor") proteins -" :- synaptobrevin (red), syntaxin-1 (yellow), and SNAP-25(green) with Ca++ sensor – synaptotagmin(violet) fusion of vesicle membrane with plasma membrane + release of neurotransmitter
- 13. • Acetylcholine, glutamate,epinephrine and nor epinephrine are released from presynaptic neuron by calcium mediated exocytosis • Epinephrine:- anaphylactic shock cardiac resuscitation along with local anaesthetic epistaxis
- 14. Stimulation :-insulin secretion from pancreatic beta cells by sulfonylureas and meglitinide analogues in diabetes mellitus Inhibition :- glutamate secretion from presynaptic neuron by gabapentin and lamotrigine in partial and generalised tonic-clonic seizures
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- 17. Centrally actingmuscle relaxant:- baclofen GABAB receptor activation Increase K+ conductance and decrease Ca++ conductance Hyperpolarization of neurons Decrease release of excitatory neurotransmitters • Relieve painful spasticity in multiple sclerosis and spinal injuries • treatment of trigeminal neuralgia, tardive dyskinesia
- 18. Directly actingmuscle relaxant:- dantrolene Reduce depolarization- induced Ca++ release from sarcoplasmic reticulum Drug of choice in malignant hyperthermia( genetic condition featuring persistent release of Ca++ from SR due to mutation) • Relieve spasticity in spinal cord injuries, multiple sclerosis and cerebral palsy
- 19. Botulinum toxintype A • degrades SNAP-25(Synaptosomal-associated protein 25) and thus prevents synaptic vesicle fusion with the axon terminal(presynaptic) membrane Interfere release of acetylcholine Paralysis of muscles Uses :- several diseases associated with increased muscle tone, such as torticollis, achalasia, strabismus, blepharospasm, and other focal dystonias • approved for cosmetic treatment of facial lines or wrinkles
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- 21. Calcium channel blockers Classification :- Dihydropyridines : nifedipine, nimodipine, nicardipine, amlodipine, nitrendipine Non-dihydropyridines : verapamil, diltiazem Mechanism :- prolonged closure of inactivation gate of voltage gated calcium channels L- type Smooth muscle relaxation Negative ionotropic, chronotropic and dromotropic action
- 22. • Cardiac depressantaction – verapamil > diltiazem > nifedipine • Coronary vasodilatation – nifedipine > verapamil > diltiazem • Peripheral + pulmonary vasodilatation -- nifedipine > verapamil > diltiazem Therapeutic uses :- Angina, hypertension, post infarct protection
- 23. Nitrates and Phosphodiaesterase– 5 inhibitors
- 24. Therapeutic uses Nitrates:- nitroglycerine, isosorbide dinitrate, isosorbide mononitrate Angina pectoris Heart failure Myocardial infarction Cyanide poisoning Phosphodiaesterase – 5 inhibitors :-sildenafil ,vardenafil , tadalafil Erectile dysfunction Pulmonary hypertension
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- 26. Inositol IP PIPPIP2
- 27. Lithium • In manicdepressive bipolar psychoses, lithium inhibits signal transduction in overactive neurons by blocking the conversion of IP2 (inositol biphosphate) to IP1 and IP1 (inositol monophosphate) to inositol • Narrow therapeutic window : 0.5-1.5 mEq/L • Side effects:- - inhibition of TSH activated adenylyl cyclase – hypothyroidism - Inhibition of ADH stimulated adenylyl cyclase – diabetes insipidus
- 28. NMDA receptor • Glutamatereceptor –excitatory • NMDA (N-Methyl-D-aspartate) antagonist 1. Felbamate – epilepsy 2. Memantine – alzheimer’s disease 3. Ketamine – general anaesthesia 4. Amantadine - parkinsonism
- 29. Ethosuximide prolonged closure ofinactivation gate of voltage gated calcium channels T- type Prevent the burst activity of thalamic relay neurons that activate the cortical cells in absence seizures
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- 33. • Therapeutic concentration: 0.5-1.4 ng/ml(digoxin) Therapeutic uses :- Congestive heart failure Atrial fibrillation Arial flutter Paroxysmal supraventricular tachycardia
- 34. Inodilators (phosphodiaesterase -3 inhibitors) • Inamrinone • Milrinone • Levosimendan • Enoximone - In acute heart failure
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- 36. Action potential innodal tissues(SA node & AV node)
- 37. Calcium channel blockersin arrhythmia Calcium channel blockers ( verapamil, diltiazem) Block L – type calcium channels Slow calcium dependent depolarization (0 phase) + decreased slope of phase 4 depolarization in nodal tissues Prolonged ERP of AV node AV nodal reentry arrhythmia
- 38. Therapeutic uses:- Paroxysmal supraventricular tachycardia Atrial fibrillation Arial flutter
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- 40. Normal serum level: 8.7- 10.2 mg/dL
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- 42. Etiology : •Excessive PTH production Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma) Inactivating mutations in the CaSR (familial hypocalciuric hypercalcemia) Alterations in CaSR( calcium sensing receptor) function (lithium therapy) • Excessive 1,25(OH)2D production Vitamin D intoxication
- 43. • Primary increasein bone resorption Hyperthyroidism Immobilization • Excessive calcium intake Milk-alkali syndrome Total parenteral nutrition
- 44. Medical management:- •forced diuresis with loop diuretics • Biphosponates : - Inhibition of osteoclastic resorption of bones by accelerating their apoptosis - Suppression of osteoclast precursors by inhibition of interleukin-6 release - 1st generation : etidronate, clodronate, tiludronate 2nd generation : alendronate, pamidronate, ibandronate 3rd generation : risedronate, zolendronate, neridronate, oxidronate
- 45. • Calcitonin : -inhibit osteoclastic bone resorption by direct action • Glucocorticoids : - Antagonise intestinal transport of Ca++ by calcitriol - Useful in vitamin D intoxication and familial hypocalciuric hypercalcemia • Dialysis
- 46. Cinacalcet • Calcimimetic activation ofcalcium sensing receptors(CaSR) over parathyroid cells Block PTH secretion Used in • Secondary hyperparathyroidism in CRF • Parathyroid carcinoma
- 47. Osteoporosis Pathophysiology :- •Bone remodeling has two primary functions: (1) to repair microdamage within the skeleton to maintain skeletal strength(bone matrix production: osteoblast) and (2) to supply calcium from the skeleton to maintain serum calcium(bone resorption: osteoclast). • Acute demands for calcium involve osteoclast-mediated resorption as well as calcium transport by osteocytes • Chronic demands for calcium result in secondary hyperparathyroidism, increased bone remodeling, and overall loss of bone tissue increased risk of fracture
- 48. Management :- •Calcium plus vitamin D preparations • Biphosphonates • SERM(Selective estrogen receptor modulator) like tamoxifen, raloxifene in postmenopausal osteoporosis • Calcitonin • Recombinant PTH (rPTH – teriparatide)
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- 50. Etiology :- Low parathyroid hormone levels : • Parathyroid destruction Surgical Radiation Infiltration by metastases or systemic diseases Autoimmune • Reduced parathyroid function Activating CaSR mutations
- 51. High parathyroidhormone levels : Vitamin D deficiency or impaired 1,25(OH)2D production/action Renal insufficiency with impaired 1,25(OH)2D production PTH receptor mutations Pseudohypoparathyroidism (G protein mutations) • Drugs Calcium chelators Inhibitors of bone resorption (bisphosphonates) Altered vitamin D metabolism (phenytoin, ketoconazole)
- 52. Management :- •Calcium preparations Calcium citrate Calcium lactate Calcium gluconate Calcium carbonate Calcium carbonate + vitamin D2
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- 54. YEAR Drug ClassIndication 2008 clevidipine CCB hypertension 2009 tadalafil PD-5 inhibitor Pulmonary hypertension capsaicin TRPVI antagonist Postherpetic neuralgia 2010 denosumab RANKL inhibitor osteoporosis 2012 pregabalin VDCC inhibitor Neuropathic pain avanafil PD-5 inhibitor erectile dysfunction 2013 nimodipine CCB Post-SAH ischemia
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Editor's Notes
- #29 Ketamine-phencyclidine,zinc, magnesium,pcp-inhibitory; glycine- decreased desensitization