Hypertension PDF - Basic Principles of Pharmacology

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Hypertension and the autonomic nervous system Treatment and mechanism of action YFRM202 2  Lecture Overview In this lect...

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Hypertension and the autonomic nervous system Treatment and mechanism of action YFRM202 2  Lecture Overview In this lecture you can expect to learn about the relationship between blood pressure and the autonomic nervous system. You have previously learned about beta-blockers and their effects on the cardiovascular system. In this lecture you will build upon that knowledge and further explore how blood pressure is regulated and the effects of drugs. Throughout this lecture it will become clear that drugs affecting the autonomic nervous system influence blood pressure. 3  Learning Outcomes At the end of this lecture, you should be able to:  Describe the physiology of the ANS and adrenal gland as they relate to cardiovascular function and control.  Describe the location and functions of the α, β1 and β2 receptors in the cardiovascular system.  Describe the effects of the autonomic nervous system on the peripheral vascular system and peripheral vascular resistance  Describe the effects of the sympathetic and parasympathetic nervous systems on cardiac function and the peripheral vascular system.  Draw a diagram to demonstrate which nerves, receptors and neurotransmitters are involved.  Define hypertension  Identify the types of hypertension and their possible causes i.e. Primary and secondary HPT  Describe where drugs can be used to target the autonomic nervous system receptors and their mechanism of action to decrease the blood pressure in patients with HPT.  Describe the actions and effects of the beta and alpha blockers. 4  Determinants of blood pressure BLOOD PRESSURE = Cardiac Output (CO) x Peripheral vascular resistance (PVR) BP = CO x PVR CARDIAC OUTPUT = Stroke Volume (SV) x Heart Rate (HR) CO = SV x HR Note: SV = EDV – ESV (≡ Ejec on frac on L Ven) Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Figure 10.1. Page 106-107. Figure source: Lippincott Illustrated Reviews: Pharmacology – Figure 17.3 - page 227 Cardiac output, which is the product of stroke volume and heart rate, is increased by sympathetic stimulation via activation of β1-adrenoceptors in the heart, and it is influenced by the kidneys through their regulation of blood volume, which is one of the factors determining the cardiac filling pressure and stroke volume. PVR is chiefly determined by the resistance to blood flow through the arterioles, whose cross-sectional area depends on arteriolar smooth muscle tone in the various vascular beds. Via activation of α1-adrenoceptors, the sympathetic nervous system stimulates arteriolar smooth muscle contraction, and this leads to vasoconstriction. Blood-borne substances such as vasopressin and angiotensin II also cause vasoconstriction, whereas locally released adenosine, serotonin, endothelin, and prostaglandins also affect arteriolar smooth muscle tone. These substances serve to regulate blood flow through the tissues and influence arterial pressure. 5  Blood pressure control Sympathetic Kidneys nervous system The sympathetic nervous system provides short-term control of blood pressure through the baroreceptor reflex The kidneys are responsible for the long-term control of blood pressure via regulation of plasma volume and the renin-angiotensin- aldosterone system (RAAS) Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Figure 10.1. Page 106-107. The sympathetic nervous system provides short-term control of blood pressure through the baroreceptor reflex. This reflex modulates sympathetic stimulation of cardiac output and PVR and adjusts blood pressure in response to postural changes and altered physical activity. The kidneys are responsible for the long-term control of blood pressure via regulation of plasma volume and the renin-angiotensin-aldosterone axis. By these mechanisms, the sympathetic system and kidneys maintain arterial blood pressure within a fairly narrow range when a person is at rest, and they adjust blood pressure appropriately in response to postural changes and physical activity. 6  Baroreceptor control – baroreceptor reflex Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Figure 10.1. Page 106-107. From https://www.cvphysiology.com/Blood%20Pressure/BP012 Arterial blood pressure is normally regulated within a narrow range, with a mean arterial pressure typically ranging from 85 to 100 mmHg in adults. It is important to tightly control this pressure to ensure adequate blood flow to organs throughout the body. This is accomplished by negative feedback systems incorporating pressure sensors (i.e., baroreceptors) that sense the arterial pressure. The most important arterial baroreceptors are located in the carotid sinus (at the bifurcation of external and internal carotids) and in the aortic arch (Figure 1). These receptors respond to stretching of the arterial wall so that if arterial pressure suddenly rises, the walls of these vessels passively expand, which increases the firing frequency of action potentials generated by the receptors. If arterial blood pressure suddenly falls, decreased stretch of the arterial walls leads to a decrease in receptor firing. The carotid sinus baroreceptors are innervated by the sinus nerve of Hering, which is a branch of the glossopharyngeal nerve (IX cranial nerve). The glossopharyngeal nerve synapses in the nucleus tractus solitarius (NTS) located in the medulla of the brainstem. The aortic arch baroreceptors are innervated by the aortic nerve, which then combines with the vagus nerve (cranial nerve X) traveling to the NTS. The NTS modulates the activity of sympathetic and parasympathetic (vagal) neurons in the medulla, which in turn regulate the autonomic control of the heart and blood vessels. 7 Although the baroreceptors can respond to either an increase or decrease in systemic arterial pressure, their most important role is responding to sudden reductions in arterial pressure (Figure 3). This can occur, for example, when a person suddenly stands up or following blood loss (hemorrhage). A decrease in arterial pressure (mean, pulse or both) results in decreased baroreceptor firing. Autonomic neurons within the medulla respond by increasing sympathetic outflow and decreasing parasympathetic (vagal) outflow. Under normal physiological conditions, baroreceptor firing exerts a tonic inhibitory influence on sympathetic outflow from the medulla. Therefore, acute hypotension results in a disinhibition of sympathetic activity within the medulla, so that sympathetic activity originating within the rostral ventrolateral medulla increases. These autonomic changes cause vasoconstriction (increased systemic vascular resistance, SVR), tachycardia and positive inotropy. The latter two changes increase cardiac output. Increases in cardiac output and SVR lead to a partial restoration of arterial pressure. It is important to note that baroreceptors adapt to sustained changes in arterial pressure. For example, if arterial pressure suddenly falls when a person stands, the baroreceptor firing rate will decrease; however, after a period of time, the firing returns to near normal levels as the receptors adapt to the lower pressure. Therefore, the long-term regulation of arterial pressure requires activation of other mechanisms (primarily hormonal and renal) to maintain normal blood pressure. 7  Central control of BP: The Baroreceptor Reflex When BP is too high, the increased arterial pressure activates stretch receptors (Baroreceptors) in the aortic arch and carotid sinus Impulses are sent to the brainstem vasomotor center, resulting in: Ac va on of the vagal motor nucleus → ↑ parasympathe c ou low → ↓ HR → ↓ CO → ↓ BP ↓ S mula on of spinal intermediolateral neurons that ac vate sympathe c preganglionic fibers → ↓ sympathe c s mula on of the heart and blood vessels → ↓ CO & PVR → ↓ BP Brenner & Stevens’ Pharmacology. 2023. Chapter 8 Sympathetic neuropharmacology and adrenergic agonists. Figure 8.2. Page 84. Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Page 106. The baroreceptor reflex. 1, Increased arterial pressure activates stretch receptors in the aortic arch and carotid sinus. 2, Receptor activation initiates afferent impulses to the brainstem vasomotor center (VMC). 3, Via solitary tract fibers, the VMC activates the vagal motor nucleus, which increases vagal (parasympathetic) outflow and slows the heart. At the same time, the VMC reduces stimulation of spinal intermediolateral neurons that activate sympathetic preganglionic fibers, and this decreases sympathetic stimulation of the heart and blood vessels. The intermediolateral nucleus, which forms a lateral horn, is composed of sympathetic preganglionic neurons. By this mechanism, drugs that increase blood pressure produce reflex bradycardia. Drugs that reduce blood pressure attenuate this response and cause reflex tachycardia 8  Central control of BP – baroreceptor reflex Brenner & Stevens’ Pharmacology. 2023. Chapter 8 Sympathetic neuropharmacology and adrenergic agonists. Figure 8.2. Page 84. Figure 8.2 The baroreceptor reflex. 1, Increased arterial pressure activates stretch receptors in the aortic arch and carotid sinus. 2, Receptor activation initiates afferent impulses to the brainstem vasomotor center (VMC). 3, Via solitary tract fibers, the VMC activates the vagal motor nucleus, which increases vagal (parasympathetic) outflow and slows the heart. At the same time, the VMC reduces stimulation of spinal intermediolateral neurons that activate sympathetic preganglionic fibers, and this decreases sympathetic stimulation of the heart and blood vessels. By this mechanism, drugs that increase blood pressure produce reflex bradycardia. Drugs that reduce blood pressure attenuate this response and cause reflex tachycardia. 9  Innervation of the CV system by the ANS Direct innervation by the sympathetic and parasympathetic nervous systems of: Cardiac smooth muscle Vascular smooth muscle SA and AV nodes Innervation of the adrenal medulla causes release of NA and Ad which binds to adrenergic receptors, stimulating the sympathetic nervous system Netter’s Illustrated Pharmacology. 2014. Chapter 2 Drugs Used to Affect the Autonomic and Somatic Nervous Systems. Figure 2.15. Page 51. Since the sympathetic and parasympathetic divisions have opposing actions, if a drug increases the sympathetic division, it decreases the parasympathetic response, and vice versa. If a drug blocks the sympathetic division, it ends up increasing the parasympathetic response. 10  Innervation of the CV system by the ANS Brenner & Stevens’ Pharmacology. 2023. Chapter 6 Parasympathetic, neuromuscular pharmacology and cholinergic agonists. Figure 6.1. Page 60 Figure 6.1 Neurotransmission in the autonomic and somatic nervous systems. The parasympathetic nervous system consists of cranial and sacral nerves with long preganglionic and short postganglionic fibers. The sympathetic nervous system consists of thoracic and lumbar nerves with short preganglionic and long postganglionic fibers. The sympathetic system includes the adrenal medulla, which releases norepinephrine and epinephrine into the blood. The somatic nervous system consists of motor neurons to the skeletal muscle. α, α-Adrenoceptors; ACh, acetylcholine; β, β-adrenoceptors; E, epinephrine; M, muscarinic receptors; N, nicotinic receptors; NE, norepinephrine. 11  Location and effects of the ANS receptors on the CV system Subtype Location Function Heart: SA and AV node, Stimulation of the heart: ↑ HR and force of atrial and ventricular muscle contraction, ↑ automaticity β1 Juxtaglomerular cells of the Activation of the renin-angiotensin-aldosterone kidney system Smooth muscle of blood vessels (Mainly in larger β2 Vasodilation blood vessels in muscles used for flight and fight) Smooth muscle of blood vessels (Diffuse throughout α1 the arterial system e.g. Vasoconstriction viscera, skin , brain , bladder neck and prostate) Negative feedback loop that inhibits further release α2 Presynaptic neurons of NA & ACh Heart: SA and AV node, ↓ HR and force of contraction, AV block ( M2 atrial muscle Parasympathetic) Rang & Dale’s Pharmacology. 2024. Chapter 13 Chemical mediators and the autonomic nervous system Figure 13.1 The main effects of the autonomic nervous system. Page 172 Rang and Dale’s pharmacology. 2024. Chapter 15. Table 15.1 Page 207. Brenner & Stevens’ Pharmacology. 2023. Chapter 8 Sympathetic neuropharmacology and adrenergic agonists Table 8.1 Properties of adrenergic, dopamine and imidazoline receptors. Page 85. 12  Systemic control of blood pressure Lippincott Illustrated Reviews: Pharmacology – Figure 17.4 - page 227 Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Page 107 BP is mainly controlled by 2 systems: Sympathetic NS and RAAS. From a systemic hemodynamic perspective, blood pressure is regulated primarily by the sympathetic nervous system and the kidneys through their influence on cardiac output and peripheral vascular resistance (PVR). Cardiac output depends on heart rate and EDV – ESV and the ejection fraction of the EDV. Vasoactive and other substances produced within the blood vessel wall also have a substantial role in the regulation of blood pressure and in the pathophysiology of hypertension. 13  Hypertension Definition and treatment options YFRM202 14  What is hypertension? Definition :- The current definition of hypertension (HTN) is systolic blood pressure (SBP) values of 130mmHg or more and/or diastolic blood pressure (DBP) more than 80 mm Treatment of HPT - persistent BP readings of 140/90mmHg or more should undergo treatment with the usual therapeutic target of 130/80mmHg or less. Types of HPT A. Primary / Idiopathic/ Essential is the commonest type – multicausal and associated with other lifestyle illnesses e.g. diabetes , obesity , hypercholesterolaemia – i.e. Metabolic syndrome. Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Page 105- 106. No clinical reason to want to cause bronchoconstriction or vasoconstriction in skeletal muscle 15  What is hypertension? Types of HPT cont. B. Secondary HPT – results from a secondary cause such as the following :- Kidney failure – acute and chronic , renovascular disease Adrenal disorders – pheochromocytoma, Cushing’s , hyperaldosteronism Thyroid disease - hyperthyroidism ; Parathyroid disease – hyper parathyroidism Alcohol and recreational drugs e.g. amphetamines , caffeine , nicotine , etc Medication e.g. Sex Hormones e.g. OCs, corticosteroids , NSAIs ; Pregnancy Induced Hypertension and Pre-eclampsia /Eclampsia Others Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Page 105- 106. 16  Sites of action: antihypertensive drugs Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Page 107. Figure 10.1 Physiologic control of blood pressure and sites of drug action. Blood pressure is the product of cardiac output and peripheral vascular resistance (PVR). These parameters are regulated on a systemic level by the sympathetic nervous system and the kidneys. Antihypertensive drugs act to suppress excessive sympathetic activity and modify renal function to counteract the mechanisms responsible for hypertension. Sites of action of the following drugs are shown: 1, vasodilators; 2, β-adrenoceptor antagonists (β- blockers); 3, α-adrenoceptor antagonists (α-blockers); 4, angiotensin receptor antagonists; 5, centrally acting sympatholytics; 6, angiotensin-converting enzyme (ACE) inhibitors; 7, direct renin inhibitors; and 8, diuretics. The vasodilators, sympatholytic drugs, and angiotensin inhibitors reduce PVR; β-adrenoceptor blockers primarily reduce cardiac output; and diuretics promote sodium excretion and reduce blood volume. 17  Mechanism of action: beta-blockers Block β1 receptors in heart ↓ HR and force of contrac on → ↓ cardiac output → ↓ BP Block β1 receptors in juxtaglomerular cells of the kidney ↓ renin release → ↓ RAAS ac va on → ↓ BP Lippincott Illustrated Reviews: Pharmacology – Figure 17.8 - page 230 Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Page 106- 107. The β-blockers lower blood pressure by blocking β1-adrenoceptors in the heart and other tissues. Blockade of cardiac β1-receptors reduces cardiac output by decreasing the heart rate and contractility. Blockade of β1-receptors in renal juxtaglomerular cells inhibits renin secretion, which in turn reduces the formation of angiotensin II and the subsequent release of aldosterone. The drugs also appear to reduce sympathetic outflow from the central nervous system. Hence, β-blockers have actions at several sites affecting blood pressure. 18  Mechanism of action: alpha-blockers Antagonis Vasodilati m of α1 on ↓ PVR ↓ BP receptors Problems associated with the use of α1 receptor antagonists: Orthostatic hypotension Reflex sympathetic stimulation ↑ HR, contrac lity, and circula ng NA levels leads to ↑ myocardial O2 requirements Activation of RAAS and fluid retention Brenner & Stevens’ Pharmacology. 2023. Chapter 10 Antihypertensive drugs. Page 109- 110. Selective α1-blockers, such as doxazosin, prazosin, and terazosin, are not recommended for the initial treatment of high blood pressure but can be added to other drugs when blood pressure is not adequately controlled. Although they effectively inhibit sympathetic stimulation of arteriolar contraction, leading to vasodilation and decreased vascular resistance, these drugs have several disadvantages. The α1-blockers may evoke reflex activation of the sympathetic nervous system and can increase the heart rate, contractile force, and circulating norepinephrine levels and thereby increase myocardial oxygen requirements. Because they activate the renin-angiotensin-aldosterone system and cause fluid retention, α1-blockers are often given with a diuretic. The α1-blockers can also cause orthostatic hypotension, and the initial administration of an α1-blocker may cause “first dose” syncope in some patients, particularly patients taking a diuretic. This can be prevented by beginning treatment with a low dose of the blocker at bedtime and withholding the diuretic for a day until the body adjusts to the lowered blood pressure. 19  Mechanism of action: alpha-blockers Brenner & Stevens’ Pharmacology. 2023. Chapter 9 Adrenergic receptor agonists. Figure 9.3 A comparison of the effects on heart rate. Page 99. Prazosin, a selective α1-blocker, does not block α2-adrenoceptor–mediated inhibition of norepinephrine release. Therefore, prazosin causes less tachycardia than does phentolamine. α1, α1-adrenoceptors. 20 Brenner & Stevens’ Pharmacology. 2023. Chapter 9 Adrenergic receptor agonists. Figure 9.2 Page 98. Cardiovascular effects of α1-adrenoceptor antagonists (solid line) and β1-adrenoceptor antagonists (dotted line) in patients with hypertension. A, The α1-blockers reduce peripheral vascular resistance, whereas β1-blockers can cause a slight increase in peripheral resistance as a result of reflex vasoconstriction. B, The β1-blockers reduce cardiac output, whereas the α1-blockers can increase cardiac output by decreasing cardiac afterload and aortic impedance to ventricular ejection of blood. C, Both α1- blockers and β1-blockers reduce mean arterial blood pressure. 21  Checklist Can you...  Describe the physiology of the ANS and adrenal gland as they relate to cardiovascular function and control?  Describe the location and functions of the α, β1 and β2 receptors in the cardiovascular system?  Describe the effects of the autonomic nervous system on the peripheral vascular system and peripheral vascular resistance?  Describe the effects of the sympathetic and parasympathetic nervous systems on cardiac function and the peripheral vascular system?  Draw a diagram to demonstrate which nerves, receptors and neurotransmitters are involved?  Define hypertension?  Identify the types of hypertension and their possible causes i.e. Primary and secondary HPT?  Describe where drugs can be used to target the autonomic nervous system receptors and their mechanism of action to decrease the blood pressure in patients with HPT?  Describe the actions and effects of the beta and alpha blockers? 22  References Brenner & Stevens’ Pharmacology. 2023. Chapter 9 Adrenergic receptor antagonists. Page 95-102 & Chapter 10 Antihypertensive drugs. Page 105-107. Rang and Dale’s Pharmacology. 2024. Chapter 15 Noradrenergic transmission. Page 205-224. 23  Feedback Please be kind enough to take a minute and rate this lesson and provide a little feedback to help us gain a better understanding of your learning experience. Let us know what you really enjoyed and what we can do better for you. Click on the link at the bottom of the lesson page on I-learn to provide feedback for this lesson. +- (2mins) 24 25 26