Drugs affecting cyclic GMP

Question 1

Two major cGMP-generating pathways

Answer 1

1. NO&raquo_space;> soluble guanylyl cyclase&raquo_space;> cGMP
2. natriuretic peptide&raquo_space;> particulate guanylyl cyclase&raquo_space;> GMP

Major downstream effectors after cGMP are PKG and cyclic nucleotide gated ion channels
cGMP action terminated by catalytic breakdown- phosphodiesterases

Question 2

Major cardiovascular actions of cGMP

Answer 2

Increases vascular smooth muscle relaxation
Decreases platelet aggregation
Decreases endothelial permeability
Decreases cell proliferation/ growth

Question 3

Actions of cGMP in vascular smooth muscle and platelets

Answer 3

In vascular smooth muscle, an increase in cGMP/PKG promotes relaxation
In platelets, an increase in cGMP/PKG inhibits aggregation

Question 4

Nitrovasodilators

Answer 4

Nitrovasodilators are pro drugs
React with SH groups to release NO
Smooth muscle relaxation, via activation of sGC and elevation of cGMP
Antiplatelet actions of NO/cGMP
Lusitropic action of NO (increases diastolic relaxation&raquo_space;> increased filling)

Question 5

Nitrovasodilators for angina

Answer 5

Nitrates (GTN, ISMN, ISDN) are used primarily to treat stable angina and variant angina
Sublingual formulations provide rapid onset of action to prevent or terminate attacks
Long acting formulations are used with other drugs for long-term prophylaxis

Question 6

Actions of nitrates

Answer 6

Venodilatation&raquo_space;> decreased cardiac preload&raquo_space;> decreased contractility/ O2 consumption
Coronary/collateral dilatation&raquo_space;> increased myocardial perfusion&raquo_space;> increased O2 supply

Question 7

Nitrate tolerance

Answer 7

Repeated administration of NO donors in experimental preparations leads to tachyphylaxis (due to depletion of free SH groups in tissues)
Tolerance develops rapidly with long-acting formulations or continuous IV infusions
Development of eccentric dosing schedules e.g. patch on for 16 h, off for 8 h
Few problems with prn use of nitrates

Question 8

Use of nitrates in emergencies

Answer 8

Used in acute coronary syndromes and or acute decompensation in heart failure (IV injection of GTN/ ISDN)
Sodium nitroprusside has particular use in the controlled lowering of BP in hypertensive emergenices, or in surgical anaesthesia (IV injection, titrated to BP response, risk of CN accumulation and intoxication)

Question 9

Natriuretic peptide family

Answer 9

ANP and BNP secreted in response to marked haemodynamic and fluid overload
BNP is a diagnostic and prognostic marker of ventricular dysfunction
ANP and BNP secretion represents the endocrine activity of the heart
Vasodilator&raquo_space;> decrease afterload
Natriuretic/ diuretic&raquo_space;> decrease venous pressure&raquo_space;> decrease preload

Question 10

Therapeutic manipulation of BNP

Answer 10

Recombinant human BNP = nesiritide
Licensed in US for treatment of acute decompensation in heart failure
Possible increased risk of renal failure and mortality
Neutral endopeptidase inhibitor drugs under development to potentiate activity of endogenous ANP and BNP

Question 11

PDE-V inhibitors

Answer 11

PDE-V inhibitors are primarily licensed for treatment of erectile dysfunction
Important evolving applications in pulmonary hypertension: licensed indication for sildenafil
PDE-V is also highly expressed in pulmonary vasculature so relatively selective vasodilatation