intracellular and extracellular relation to pharmacotherapeutics

1. 2

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 in the field of
voltage-gated calcium channels :-
A. Sir Bernard Katz
B. Susumu Hagiwara
C. Harald Reuter

4. Signal transduction
pathways

5. G protein coupled receptors

6. Adenylyl cyclase: cAMP
Activation of 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

8. Phospholipase C: IP3-DAG

9. Phospholipase C : IP3-DAG
• Adrenergic- α1
• Histamine-H1
• Muscarinic-M1,M3
• 5-HT2
• Vasopressin-Oxytocin
• Angiotensin-AT1
• Prostaglandin-FP, EP3
• Leukotriene
• EndothelinA , endothelinB

10. Calcium mediated
exocytosis

12. Ca++ triggers binding of 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

15. Muscular system

16. Muscle contraction

17.  Centrally acting muscle 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 acting muscle 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 toxin type 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

20. Vascular system

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 depressant action – 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

25. Nervous system

26. Inositol IP PIP PIP2

27. Lithium
• In manic depressive 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
• Glutamate receptor –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 of inactivation gate of voltage gated calcium
channels T- type
Prevent the burst activity of thalamic relay neurons that activate
the cortical cells in absence seizures

30. Heart

31. Contraction

32. Digitalis

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

35. Rate & Rhythm

36. Action potential in nodal tissues(SA
node & AV node)

37. Calcium channel blockers in
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

39. Calcium homeostasis

40. Normal serum level : 8.7- 10.2 mg/dL

41. Hypercalcemia

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 increase in 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 of calcium 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)

49. Hypocalcemia

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 parathyroid hormone 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

53. Recently FDA approved
drugs

54. YEAR Drug Class Indication
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

55. THANK YOU