CVS Pharm 1x PDF

Introduction to cardivascular pharmacology Prof. Zafer Gören, MD, PhD  Cardiac function is controlled by the autonomic nervous system (i.e., the sympathetic and the parasympathetic nervous systems), which act via adrenoceptors and muscarinic acetylcholine Cardiac funct...

Introduction to cardivascular pharmacology Prof. Zafer Gören, MD, PhD  Cardiac function is controlled by the autonomic nervous system (i.e., the sympathetic and the parasympathetic nervous systems), which act via adrenoceptors and muscarinic acetylcholine Cardiac function are not obly receptors, respectively. regulated by autonomic controls od symapthic and parasympathetic, they are aslo  At least nine adrenoceptor subtypes and five requalted by physiological facters like aging and congestive heart muscarinic receptor subtypes exist. failure diseases  The autonomic control of cardiac function can be dynamically regulated by physiological factors such as aging and by disease states such as congestive heart failure.  α1-adrenoceptors  Three subtypes of α1-adrenoceptors have been A1a has a vasoconstriction effect identified pharmacologically and through molecular primarily cloning: α1A (formerly α1c), α1B, and α1D. Why dose A1a has  Stimulation of α1a receptors produce increase in PLC, the primary vasoconstriction PLA2, Ca2+ channel activity and Na+/H+ exchange. ability? α1a are located in the heart, liver, smooth muscle, blood vessels, lung, vas deferens, prostate, cerebellum, cortex and the hippocampus.  Which one of the receptors below is most commonly found on heart ?  Stimulation of alfa1b receptors produce increase in PLC, PLA2, Ca2+ channel activity and Na+/H+ exchange.  1b are located in kidney, spleen, lung, blood vessels, cortex 1b receptors are the most abundant subtype in the heart they promote “cardiac growth and structure”. Hence the beta blocker anti remodelling benefints Beacuse a1a and A1d receptor are potent vaconsticter founf in prostate any dysfunction in them will lead to erectile Blockage of dysfunction which one the receptors below would cause vasodilation in 1d receptors also use PLC, PLA2, Ca2+ aorta and coronary artery? channel activity and Na+/H+ exchange as effector systems.  They are found in the platelets, prostate, aorta, coronary artery, cortex, hippocampus.  Predominant receptor causing “vasoconstriction in aorta and coronary artery”  2 receptors A2a recpter do not cause vasoconstriction directly. They cause vasoconstriction by inhabiting sympathetic neurons (we only have sympathetic fibers in vessels ) Stimulation of 2a receptors produce decrease in adenylate cyclase activity, decrease in cAMP and PKA activity.  They are located in platelets, sympathetic neurons, autonomic ganglia, pancreas, coronary/CNS vessels, Locus ceruleus, brainstem and spinal cord.  They are predominant inhibitory receptor on sympathetic neurons  They produce “vasoconstriction of small procapillary vessels in the skeletal muscle” Stimulation of 2b receptors produce decrease in adenylate cyclase activity, decrease in cAMP and PKA activity.  They are located in liver, kidney, blood vessels, Coronary/CNS vessels, diencephalon, pancreas. They are predominant receptors “mediating 2 vasoconstriction”. Stimulation of 2c receptors produce decrease in adenylate cyclase activity, decrease in cAMP and PKA activity.  They are located in basal ganglia, cortex cerebellum and hippocampus.  They are predominant receptors modulating “dopamine neurotransmission” and “inhibiting hormone release from adrenal medulla”.  -adrenergic receptors Three functional  receptors exist and stimulation of 1 receptors produce increase in adenylate cyclase activity, increase in cAMP and intracellular Calcium. In the human heart, the ratios of 1 to 2 is about 3:2 in atria and 4:1 in ventricles  They are found predominantly in heart, kidney, adipocytes, skeletal muscle, olfactory nucleus, cortex and spinal cord.  They are the predominant receptors in heart producing “positive inotropic and chronotropic effects”.  2 receptors are located in the heart, lung, blood vessels, bronchial and GI smooth muscle, kidney, skeletal muscles, olfactory bulb, piriform cortex, cortex and hippocampus.  It is the predominant receptor in “smooth muscle relaxation” and “skeletal muscle hypertrophy”.  beta receptors are located in adipocytes, GI tract and heart  It is the predominant receptor in “metabolic effects”. The existence of a fourth type of adrenoceptor beta has been proposed. Despite intense efforts, beta has not been cloned. Current thinking is that the   represents an affinity state of  rather than a descrete receptor. Organ system Sympathetic receptors Parasympathetic receptors effect effect  SA node İncrease in Decrease in heart M2>>M3 heart rate rate 1> 2 Atria Increase Decrease in heart M2>> M3 contractility and rate, action conduction potential duration velocity 1> 2 AV node İncrease in Decrease in M2>>M3 automaticity conduction and conduction velocity and AV velocity block 1> 2 His-purkinje İncreae in Little effect M2>>M3 system automaticity and conduction velocity 1> 2 Ventricles İncrease in Slight decrease in M2>>M3 automaticity, contractility conduction velocity, contractility and pacemakers  receptors Parasympathetic receptors Sympathetic effect effect  NE and E Beta2 Receptor Alpha1 Receptor 2+ (incorporated to Gs protein and L type Ca channels) (incorporated to Gq protein) Gs stimulates Adenylate cyclase Gq acivates Phospholipase C cAMP increases PIP2=> IP3, DAG Protein kinase A is activated Protein kinase C is activated Phosphatese PP2a Phosphorylation of enzymes is also activated (+) (-) activates inactivates Myosine Light Chain Kinase Relaxation Constriction  Relative selectivity of agonists Alpha agonists: phenylephrine, methoxamine, clonidine, methylnoradrenalline Mixed alpha and beta agonists: noradrenalline, adrenalline Beta agonists: dobutamine, isoproterenol, terbutaline, albuterol, ritodrine, metaproterenol Dopamine agonists: dopamine and fenoldopam.  Individual drugs Noradrenalline: nitrogen ohne radikal -Weakly produces arrhythmia when compared to A and IPN. -It increases heart rate but bradycardia occurs as reflex Which statement is wrong. effect. Atropin reverses this. Aderbaline is commankt given with atropin to lower -Its affinity to 2 receptors is low. Affects  and  its bradycardia effect. F Noradrenaline is a receptors. vacoconstricter Isproternal is used to relax -Contracts pregnant uterus and vasoldilate Whit usage of adernaline -Used in hypotension as it is a vasoconstrictor. TPR decreases -It produces a rebound fall in blood pressure following its long-term use. Isoproterenol -The most potent SM drug that affects beta adrenoceptors. -It produces vasodilatation and bronchodilatation. -Vasodilator effect is predominant in skeletal and splanchnic vascular beds (increases blood flow) -It is used in bradycardia, heart block, shock, intoxications of -blockers.  In a patients with severe beelding risk which one of the durgs below can be given for postive intropic and chronotropic effect Adrenalline A very potent vasoconstrictor and cardiac stimulant. (+) inotropic and (+) chronotropic effect produces the rise in systolic blood pressure. Total peripheral resistance decreases: TPR= mean arterial pressure/ blood flow Dopamine -It is a catecholamine having the simplest structure. -At low doses it affects the DA receptors (0.5-2 g/kg/min). -Increases the renal blood flow -Does not affect the blood pressure. -Glomerular filtration increases. -The renal effects are DA1 receptor mediated  What is the suitable dosage for dopamin to show durateic effects ? -As the dose is increased (2-10 g/kg/min) it affects receptors. Heart rate is increased. -At very high doses (>10 g/kg/min) it also affects  receptors and produces vasoconstriction. Blood flow decreases. -Its anti-shock effect is reversed. Dopamine does not affect vasodilator 2 receptors.  Acetyl choline ACh has four primary effects on the cardiovascular system: vasodilation decrease in heart rate (negative chronotropic effect) decrease in the conduction velocity in the atrioventricular (AV) node (negative dromotropic effect) decrease in the force of cardiac contraction (negative inotropic effect) The last effect is of lesser significance in the ventricles than in the atria. Some of the above responses can be obscured by baroreceptor and other reflexes that dampen the direct responses to ACh. Although ACh rarely is given systemically, its cardiac actions are important because the cardiac effects of cardiac glycosides, anti- arrhythmic agents, and many other drugs are at least partly due to changes in parasympathetic (vagal) stimulation of the heart; in addition, afferent stimulation of the viscera during surgical interventions can reflexly increase the vagal stimulation of the heart. The intravenous injection of a small dose of ACh produces a transient fall in blood pressure owing to generalized vasodilation (mediated by vascular endothelial NO), which is usually accompanied by reflex tachycardia. A considerably larger dose is required to see direct effects of ACh on the heart, such as eliciting bradycardia or AV nodal conduction block. The generalized vasodilation produced by exogenously administered ACh is due to the stimulation of muscarinic receptors, primarily of the M3 subtype  Antimuscarinics Scopolamine is selective for “sweat,salivary and bronchial glands, eye and iris, ciliary muscle”. Atropine is selective for “heart, GIS and bronchial muscle”. - At high doses, Atropine blocks M2 receptors and inhibits the PS vagal tonus on the heart and produces tachycardia. - At low doses, bradycardia occurs due to inhibition of pre-synaptic M1 receptors. - Atropin has (+) inotropic and (+) chronotropic effects. - No effect on blood vessels observed since no PS innervation of blood vessels exists. - But Atropine can prevent vasodilator effects of PSM drugs.  M3 and endothelium mediated vasodilation Ach=>increase in Calcium calmodulin => NOS activation cGMP deactivates myosine light chain kinase (MLCK) and MLCK cannot phosphorylate MLC, so myosin and aktin cannot combine to form the contracted muscle filaments. Eventually vasodilatation occurs in vascular smooth muscles.