Transcript Cardiac glycosides

PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
Cardiac Glycosides
http://www.livescience.com/45201-tech-makes-animal-organsviable-for-transplant.html
By: Golsa Bahari-kashani
Lamis Khadir
Sukhpreet Sidhu
Namra Minhas
What are cardiac glycosides?
• Originate from the foxglove plant
(Digitalis purpurea)
• Have been used for at least 3000 years
by Ancient Egyptians, Romans, and
Early Europeans
• Treat heart conditions: congestive
heart failure and arrhythmias
• May be used to treat cancer
Diederich, M., Muller, F., & Cerella, C. (2016). Cardiac glycosides: From molecular targets to immunogenic cell death. Biochemical Pharmacology. doi:10.1016/j.bcp.2016.08.017
Structure
Structure includes :
• A glycoside (sugar)
• An aglycone [non-sugar] part
which is a steroidal moiety
• A lactone
http://www.people.vcu.edu/~urdesai/car.htm
Types of Cardiac Glycosides
Prassas, I., & Diamandis, E. P. (2008). Novel therapeutic applications of cardiac glycosides. Nature
Reviews Drug Discovery, 7(11), 926-935. doi:10.1038/nrd2682
THERAPEUTIC
USES
Congestive Heart Failure
 Failure of the heart in functioning as a pump
Causes:
•
•
•
Ischemic disease
Chronic long-term untreated hypertension
Chronic emphysema and bronchitis
 CGs increase force of cardiac contraction by
increasing intracellular Ca2+
 Effects on the heart
•
•
•
•
Heart rate slowed
Contraction is greater
Slower AV node conduction velocity
Increase in AV nodal refractory period
https://emergencymedicinecases.com/wp-content/uploads/2010/03/Ep4Acute-Heart-Failure.jpg
Atrial Fibrillation and Flutter
•
Quivering or irregular heartbeat (arrhythmia)
•
Occurs when electrical signalling in the heart is disrupted
•
Lead to rapid ventricular rate that can impair ventricular
filling
•
Digitalis compounds, such as digoxin reduce the
ventricular rate through the parasympathomimetic effect
•
Vagal activation reduces conduction of electrical impulses
within the AV node
•
Digoxin also increases the effective refractory period
within the AV node
atrial-fibrillation-s1-photo-of-atrial-fibrillation.jpg
MECHANISM
Mechanism
● inhibits Na+/K+ ATPase in cardiomyocytes by binding
to α subunit → ↑[Na+] inside cell (not pumped out)
● Na+ pumped in via Na+-Ca2+ exchanger (NCX) and
Ca2+ pumped out.
● ↑[Na+] inside cell inhibits NCX (lose concentration
gradient driving Na+ in): Ca2+not pumped out
● ↑ intracellular [Na+] → block NCX → ↑ intracellular
[Ca2+] → ↑Ca2+ reuptake by sarcoplasmic reticulum
→ ↑Ca2+ release on contraction → ↑ contractility
● Bind cardiac muscle with 10 - 1000 times higher
affinity than skeletal muscle
Bodemann, H. H. (1981). The current concept for the cardiac glycoside receptor. Clin Cardiol Clinical Cardiology, 4(5), 223-228. doi:10.1002/clc.4960040502
Digitalis Mechanism
• Na+-K+ ATPase exists in different
conformational states
• Glycoside binding site in E2P
(phosphorylated) conformation state
• Binding freezes the enzyme to stop
conformation changes and ion
transport
• Phosphorylation on inner surface of
the membrane, glycoside bound on
outside
Testa, B., & Meyer, U. A. (1995). Advances in drug research (Vol. 19). London: Academic Press.
Haviv, H., & Karlish, S. (2013). P-Type Pumps: Na ,K -ATPase.
Encyclopedia of Biological Chemistry, 681-687.
ADVERSE EFFECTS
Adverse Effects
•
Majority are dose-related
•
More marked in women than in men
•
Cardiac arrhythmia especially tachycardia and AV block
•
Toxicity common in patients with impaired renal function, lean and elderly patients
Digestive
Disorders
Neurosensory
Disorders
Cardiac Manifestations
Endocrine Effects
Anorexia, nausea,
vomiting, salivations
Headache, insomnia,
confusion,
depression, dizziness,
seizures
Beginning with
bradycardia then
extrasystole, tachycardia
or fibrillation
Related to steroid structure
of CGs high can have
metabolites with an estrogen
effect causing gynecomastia
in men
Anti-cancer Activity
● Traditionally used to treat
cardiac conditions
● CGs such as peruvoside are
promising in targeting cancers
i.e. leukemia and ovarian
cancers
● digitoxin, digoxin, bufalin, and
ouabain can stop cancer cells
from proliferating and inhibit
growth of tumours by inducing
cell death
Patel, S. (2016). Plant-derived cardiac glycosides: Role in heart ailments and cancer
management. Biomedicine & Pharmacotherapy, 84, 1036-1041.
doi:10.1016/j.biopha.2016.10.030
Summary
● Structure: steroid nucleus + sugar moiety + lactone moiety
● 2 types: cardenolides - (5-membered ring) + bufadienolides (6-membered ring)
● Therapeutic uses: mainly used to treat congestive heart failure, atrial fibrillation and flutter, and
potential uses in cancer
● Widely accepted mechanism: Inhibit Na+/K+ ATPase in cardiomyocytes by binding to its α subunit →
increased [Na+] inside cell
● ↑ intracellular [Na+] → block Na+-Ca@+ exchanger → ↑ intracellular [Ca2+] → ↑Ca2+ reuptake by
sarcoplasmic reticulum → ↑Ca2+ release on contraction → ↑ contractility
● Glycoside binding site in the Na+-Ca2+ ATPase E2P (phosphorylated) conformation state → binding
freezes the enzyme to stop conformation changes and ion transport
● Adverse effects: digestive, neurosensory, cardiac and endocrine systems
● digitoxin, digoxin, bufalin, and ouabain can stop cancer cells from proliferating and inhibit growth of
tumours by inducing cell death through the immune system
Summary
Role of CGs in cardiac disorders and cancer
Patel, S. (2016). Plant-derived cardiac glycosides: Role in heart ailments and cancer management. Biomedicine & Pharmacotherapy, 84, 10361041. doi:10.1016/j.biopha.2016.10.030
References
Diederich, M., Muller, F., & Cerella, C. (2016). Cardiac glycosides: From molecular targets to immunogenic cell death. Biochemical Pharmacology. doi:10.1016/j.bcp.2016.08.017
Prassas, I., & Diamandis, E. P. (2008). Novel therapeutic applications of cardiac glycosides. Nature Reviews Drug Discovery, 7(11), 926-935. doi:10.1038/nrd2682
Testa, B., & Meyer, U. A. (1995). Advances in drug research (Vol. 19). London: Academic Press.
Erdmann, E., Greeff, K., & Skou, J. (2013). Springer Science & Business Media.
Bodemann, H. H. (1981). The current concept for the cardiac glycoside receptor. Clin Cardiol Clinical Cardiology, 4(5), 223-228. doi:10.1002/clc.4960040502
Patel, S. (2016). Plant-derived cardiac glycosides: Role in heart ailments and cancer management. Biomedicine & Pharmacotherapy, 84, 1036-1041. doi:10.1016/j.biopha.2016.10.030
Schwinger, R. (2003). The Na, K-ATPase in the failing human heart. Cardiovascular Research, 57(4), 913-920. doi:10.1016/s0008-6363(02)00767-8
Haviv, H., & Karlish, S. (2013). P-Type Pumps: Na ,K -ATPase. Encyclopedia of Biological Chemistry, 681-687.
Congestive Heart Failure Medications. (n.d.). Retrieved from https://www2.nau.edu/~daa/lecture/chfmeds.htm
Cardiac glycosides - Therapeutic use, adverse effects and interactions - Pharmacorama. (n.d.). Retrieved from http://www.pharmacorama.com/en/Sections/NAK-ATPase-Digoxin-3.php
Atrial Fibrillation and Flutter Retrieved from http://www.cvpharmacology.com/cardiostimulatory/digitalis