L22 Hamodynamics Targets of Cardiovascular therapy.pdf

L22 : Hamodynamic Targets of Cardiovascular Therapy Drugs affecting the cardiovascular system acts on different hamodynamic targets in order to control different cardiovascular diseases like: arrythmia, heart failure, hypertension, ischemic heart diseases. These hamodynamic targets include:  Channe...

L22 : Hamodynamic Targets of Cardiovascular Therapy Drugs affecting the cardiovascular system acts on different hamodynamic targets in order to control different cardiovascular diseases like: arrythmia, heart failure, hypertension, ischemic heart diseases. These hamodynamic targets include:  Channels & Transporters; Voltage gated Ca Channels, Na Pumps  Synthetic pathways, receptors, signaling cascade of. - Autonomic Neural Control Humoral Control Local Paracrine Autocrine control We are going to discuss the pharmacological action of different drugs modulating these haemodynamic targets. I. Drugs acting on channels and transporters: 1. Calcuim Channel Blockers(CCBs): CCBs selectively inhibit the voltage-gated calcium channels on cardiac myocytes, vascular smooth muscle cells, and cells within the sinoatrial (SA) and atrioventricular (AV) nodes, preventing influx of extracellular calcium. A decrease in intracellular calcium will result in inhibition of the contractile process of the myocardial smooth muscle cells, resulting in dilation of the coronary and peripheral arterial vasculature. As a consequence, peripheral resistance is decreased leading to a decrease in systemic BP, improved oxygen delivery to the myocardial tissue, reduction of heart rate, and slowing of AV conduction. There are 2 classes of CCBs: the dihydropyridines (DHPs), which have greater selectivity for vascular smooth muscle cells than for cardiac myocytes, and the non-DHPs, which have greater selectivity for cardiac myocytes. A. Dihydropyridines : smooth muscle selective class. Because of their high vascular selectivity, these drugs are primarily used to treat hypertension. However, their powerful systemic vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia and increased inotropy), which can offset the beneficial effects of afterload reduction on myocardial oxygen demand. e.g: Nifedipine , Nifedipine retard (less tachycardia) Amlodipine (Long acting/ no tachycardia) B. Non-dihydropyridines: Myocarduim selective class is relatively selective for the myocardium, and is less effective as a systemic vasodilator drug. It causes bradycardia This drug has a very important role in treating angina and arrhythmias.e.g: Verapamil. C. Diltiazem (is intermediate between verapamil and dihydropyridines )By having both cardiac depressant and vasodilator actions, diltiazem is able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. 2. Cardiac Glycosides (Digoxin): Cardiac glycosides are potent inhibitors of cellular Na+/K+-ATPase. This ion transport system moves sodium ions out of the cell and brings potassium ions into the cell. By inhibiting the Na+/K+- ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na+- Ca++ antiporter. In the heart, increased intracellular calcium causes more calcium to be taken up and subsequently released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponinC, which increases contractility (positive inotropy). II. 1) 2) 3) 4) Drugs acting on ANS / Humoral & local control A. On Autonomic Neural Control Cardio-Selective - Blockers : Metoprolol, Atenolol, Bisoprolol, Nebivolol - Agonist : Dobutamine > Dopamine , inotropic drugs in acute HF Phosphodiestrase- Inhibitors: Milrinone ,inotropic in acute HF Ca sensitizers: inotropic drugs in acute HF B. On Humoral Control: 1) Drugs modulating Renin-Angiotensin-Aldosterone system (RAAS) Pharmacologically, the RAAS is a frequently manipulated system in managing heart failure, hypertension, diabetes mellitus, and acute myocardial infarction. ACE inhibitors (e.g., ramipril), angiotensin receptor blockers (ARBs, e.g., valsartan), and aldosterone antagonists (e.g., spironolactone) all act to decrease the effect of the RAAS. The varied mechanisms of these drugs allow their utilization in different scenarios: -ACE inhibitors inhibit the action of angiotensin-converting enzymes, thus decreasing the production of angiotensin II. The 2 systems, RAS and KKS, are controlled by the angiotensinconverting enzyme (ACE) that generates Ang II and inactivates the kinins. Inhibitors of ACE can reduce the impact of Ang II and potentiate the kinins, thus contributing to restore the cardiovascular homeostasis. The increase in level of bradykinin with ACEIs leads to more vasodilatation but can cause hyprsensitivity reaction like dry cough and angioedema. -ARBs act to block AT1 receptors, thus inhibiting angiotensin’s effect while maintaining normal levels of angiotensin; Ag synthesis is not inhibited it act on AT2 (↑ vasodilation). -Aldosterone inhibitors (e.g., spironolactone ) act as aldosterone antagonists. It works by preventing the binding of aldosterone to binding sites in the kidney, preventing of Na & water retention. A common use for ACE inhibitors or ARBs is in managing hypertension. Also they have an important role in inhibiting cardiac remodeling which will be discussed in heart failure. All these drugs can cause hyperkalemia as a side effect. 2)Drugs modulating the natriuretic peptide system (NP):Angiotensin receptor-Neprilysin inhibitors (ARNI) Sacubil/valsartan is a combination product. Sacubitril is a pro-drug that, upon activation, acts as a neprilysin inhibitor. It works by blocking the action of neprilysin, thus preventing the breakdown of natriuretic peptides. This leads to a prolonged duration of the favorable effects of these peptides. Valsartan is an ARB, and it works on blocking the RAAS system. Because neprilysin breaks down angiotensin II, inhibiting neprilysin will result in an accumulation of angiotensin II. For this reason, a neprilysin inhibitor cannot be used alone; it must always be combined with an ARB to block the effect of the excess angiotensin II. Another important substance broken down by neprilysin is bradykinin; neprilysin inhibition will also cause a build-up of bradykinin. Therefore, sacubitril cannot be used with an ACEI due to an increased risk of angioedema if ACEI and ARNI are used together or dosed in a short timeframe. C. Local Paracrine Autocrine Control: Drugs modulating NO: 1) Drugs Activating eNOS: like; oestrogen and nebivolol 2) Drugs Mimicking NO Action: Nitrovasodilators (NO DONORS) 1- Nitrates, e.g. nitroglycerine is mainly a venodilator leading to decrease in cardiac preload. Also, it is an arterial dilator that decreases the peripheral resistance and hence decreases the afterload and helps to dilate the coronaries. They are used in treatment of angina pectoris and heart failure. 2- Sodium Nitroprusside is mainly a potent arteriolar dilator used in emergency treatment of hypertension.