Cardiac Drug MOA Flashcards
52M complains of lightheadedness. PMH: Angina, DM, ED, Obesity. His meds: Nitro tablets, Sitagliptin and Metformin, Sildenafil. Vitals are in normal limits but orthostatic exam shows systole dropping by 25mmHg when pt stands. Cause of lightheadedness and Orthostatic HoTN?
Combination of Nitrates and PDE5 - both of which involve the cGMP pathway. Nitrates activate cGMP to increase the action of MLC-Phosphatase –> relaxation of smooth muscle by removing active phosphate group. PDE5 (Sildenafil) inhibits breakdown of cGMP leading to double the effect. Check the guy’s BP!
MLC-Kinase does what and MLC-Phosphatase does what? Which substances directly act on each?
MLC-Kinase phosphorylates actin and myosin to induce muscle contraction. MLC-Phosphatase dephosphorylates to cause relaxation.
Calcium-Calmodulin and cAMP act on MLC-Kinase via different channels. cGMP acts on MLC-Phosphatase.
How does Ca-Calmodulin differ from cAMP’s effects on MLC-Kinase?
Which receptors are acted on and which G-proteins?
Ca-Calmodulin actually activates MLC-Kinase to cause contraction. cAMP weirdly inhibits MLC-Kinase to cause a decrease in contraction. Hence we give CCBs to block the L-type channels to prevent Calmodulin mechanism while PGs, Adenosine, Prostacyclin, B2, D1 (Fenoldapam) agonists at the Gs receptor increase Adenylate cyclate which increases cAMP –> inhibiting MLC-Kinase.
How is PDE3 linked to cAMP? And which medication is a PDE3 inhibitor?
PDE3 normally degrades cAMP. Milirone decreases degradation of cAMP, thereby allowing it to prevent MLC-Kinase from contracting. Leads to relaxation. Unlike Gs which uses Adenylate Cyclase to increase cAMP - PDE3 inhibitors
What chemicals act on vascular endothelium to release Nitric Oxide?
AcH, alpha2 agonists, Bradykinin, Cytokines, Histamine, 5-HT, and even shear stress.
What effect does Nitric Oxide and Natriuretic Peptides have on cGMP?
Nitric Oxide increases cGMP which increases the action of MLC-Phosphatase, which dephosphorylates actin and myosin leading to relaxation. ANP, BNP, and Nesiritide do the same thing bypassing Nitric Oxide.
PDE5 and PDE3 have what in common?
Both are responsible for degradation respectively of cAMP and cGMP. Degradation of cGMP, however results in increased contraction. PDE5 inhibitors such as sildenafil reduce cGMP’s degradation, allowing it to activate MLC-Phosphatase and dephosphorylation of actin and mysoin –> smooth vascular relaxation.
What is Nesiritide and what is its use?
Recombinant hormone natriuretic peptide. Treats CHF that is worsening and causing breathing difficulty.
Which two classes of drug cause smooth muscle contraction rather than relaxation?
Gq protein agonism causes Calcium release from within the SER along with inhibition of MLC-Phosphatase - thereby causing serious contraction. alpha1, endothelin1, Vasopressin, and Angiotensin II all work with G2 agonism.
a2 agonists can also stimulate contraction (I still do not clearly understand this)