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PHARMACOLOGY II NURC 266 Lawrence Micah-Amuah Specialist Clinical Pharmacist (CARDIOLOGY) CARDIOVASCULAR SYSTEM PHARMACOLOGY OUTLINE Overview o the Cardiovascular System Diseases of the Cardiovascular System Drugs used in Cardiovascular Diseases OVERVIEW OF CARDIOVAS...

PHARMACOLOGY II NURC 266 Lawrence Micah-Amuah Specialist Clinical Pharmacist (CARDIOLOGY) CARDIOVASCULAR SYSTEM PHARMACOLOGY OUTLINE Overview o the Cardiovascular System Diseases of the Cardiovascular System Drugs used in Cardiovascular Diseases OVERVIEW OF CARDIOVASCULAR SYSTEM The Cardiovascular System comprises of two major organs; CARDIO – Heart VASCULAR – Vessels (Blood Vessels) The Heart is the major organ responsible for the pumping of BLOOD to all parts of the body The Main function of the CVS is to maintain HAEMODYNAMICS Hemodynamics is the study of the movement of blood throughout the circulatory system, along with the regulatory mechanisms and driving forces involved  The Cardiovascular System is also known as the Circulatory System. The Cardiovascular (circulatory) system has two primary functions: (1) delivery of oxygen, nutrients, hormones, electrolytes, and other essentials to cells and (2) removal of carbon dioxide and metabolic wastes from cells. In addition, the Circulatory system helps fight infection. The circulatory system has two major divisions: the pulmonary circulation and the systemic circulation. The pulmonary circulation delivers blood to the lungs. The systemic circulation delivers blood to all other organs and tissues. The systemic circulation is also known as the greater circulation or peripheral circulation. Components of the Cardiovascular System The Cardiovascular system is composed of the ✓heart and ✓blood vessels. The heart is the pump that moves blood through the arterial tree. The blood vessels have several functions: Arteries transport blood under high pressure to tissues. Arterioles are control valves that regulate local blood flow. Capillaries are the sites for exchange of fluid, oxygen, carbon dioxide, nutrients, hormones, and wastes. Venules collect blood from the capillaries. Veins transport blood back to the heart. In addition, veins serve as a major reservoir for blood. Distribution of Blood The adult circulatory system contains about 5 L of blood, which is distributed throughout the system. 9% is in the pulmonary circulation, 7% is in the heart, and 84% is in the systemic circulation. Within the systemic circulation, however, distribution is uneven: most (64%) of the blood is in veins, venules, and venous sinuses; the remaining 20% is in arteries (13%) and arterioles or capillaries (7%). The large volume of blood in the venous system serves as a reservoir. REGULATION OF CARDIAC OUTPUT In the average adult, cardiac output is about 5 L/min. Hence, every minute the heart pumps the equivalent of all the blood in the body. Determinants of Cardiac Output The basic equation for cardiac output is: CO = HR × SV where CO is Cardiac Output, HR is Heart Rate, and SV is Stroke Volume. According to the equation, an increase in HR or SV will increase CO, whereas a decrease in HR or SV will decrease CO. For the average person, heart rate is about 70 beats/min (range of 60 to 100 bpm is considered as normal) and stroke volume is about 70 mL. Multiplying these, we get 4.9 L/min—the average value for CO. REGULATION OF ARTERIAL BLOOD PRESSURE Arterial blood pressure is the driving force that moves blood through the arterial side of the systemic circulation. The general formula for ABP is: ABP = CO X TPR where ABP is Arterial Blood Pressure CO is Cardiac output TPR is Total peripheral resistance. Overview of Control Systems Under normal circumstances, arterial blood pressure is regulated primarily by two systems: the Autonomic Nervous System (ANS), the Renin-Angiotensin-Aldosterone System (RAAS) And to a less extent the Neuropeptide/hormonal system These systems differ greatly with regard to time frame of response. The ANS acts in two ways: 1. It responds rapidly (in seconds or minutes) to acute changes in blood pressure and 2. it provides steady-state control. (minute by minute) - Baroreceptors The RAAS responds more slowly, taking hours or days to influence blood pressure. The kidneys are responsible for long-term control, and hence may take days or weeks to adjust blood pressure. Arterial pressure is also regulated by a third system: a family of natriuretic peptides. These peptides come into play primarily under conditions of volume overload Rapid Control by the ANS: The Baroreceptor Reflex The baroreceptor reflex serves to maintain blood pressure at a predetermined level. When Arterial Pressure changes, the reflex immediately attempts to restore pressure to the preset value. The reflex works as follows. Baroreceptors (pressure sensors) in the aortic arch and carotid sinus sense AP and relay this information to the vasoconstrictor center of the medulla. When AP changes, the vasoconstrictor center compensates by sending appropriate instructions to arterioles, veins, and the heart. For example, when AP drops, the vasoconstrictor center causes: 1. constriction of nearly all arterioles, thereby increasing TPR; 2. constriction of veins, thereby increasing venous return; and 3. acceleration of HR (by increasing sympathetic impulses to the heart and decreasing parasympathetic impulses). The combined effect of these responses is to restore Arterial Pressure to the preset level. When AP rises too high, opposite responses occur: The reflex dilates arterioles and veins and slows the heart. The Renin-Angiotensin-Aldosterone System (RAAS) The RAAS supports Arterial Blood Pressure by causing (1) constriction of arterioles and veins and (2) retention of water by the kidneys. Vasoconstriction is mediated by a hormone named angiotensin II. Water retention is mediated in part by aldosterone through retention of sodium. Responses develop in hours (vasoconstriction) to days (water retention). Natriuretic Peptides Natriuretic peptides serve to protect the cardiovascular system in the event of volume overload, a condition that increases preload and thereby increases CO and AP. Volume overload is caused by excessive retention of sodium and water. Natriuretic peptides work primarily by: 1. reducing blood volume and 2. promoting dilation of arterioles and veins. Both actions lower AP. The family of natriuretic peptides has three principal members: Atrial natriuretic peptide (ANP), B- or Brain natriuretic peptide (BNP), and C-natriuretic peptide (CNP). ANTIDIURETIC HORMONE (ADH) ADH also known as Vasopressin plays a crucial role in regulating blood pressure by ✓Increasing water reabsorption within the kidneys to increase blood volume ✓causing blood vessels to constrict (at high concentrations) It is released in response to low blood volume, low blood pressure conditions which occurs during dehydration, hemorrhage, hypernatremia ADH is also released in response to thirst, nausea, vomiting and pain It is synthesized by the Hypothalamus and stored in the posterior pituitary where it is released into the blood stream ADH when released binds to the Vasopressin-2 receptor (V2R) in the principal cells to induce the expression of water transport proteins (aquaporins) in the late DCT and CCT to increase water reabsorption. At higher concentrations, ADH binds to Vasopressin-1a receptors on the vascular smooth muscles which then triggers a signaling cascade (PLC, ITP pathway)leading to increased intracellular Ca levels. This causes smooth muscle contraction and subsequent vasoconstriction. This mechanism essentially redirects blood flow to vital organs CARDIOVASCULAR DISEASES Cardiovascular Diseases are conditions that affect the structures and functions of the heart and blood vessels leading to loss of ORGAN and SYSTEMIC dysfunctions in the body. Leading cause of morbidity and mortality worldwide According to the World Health Organization, an estimated 17.9 million people died from Cardiovascular diseases in 2019. This represents 32% of all global deaths CARDIOVASCULAR DISEASES Hypertension Angina Myocardiac Infarction Arrythmias Coronary Artery Diseases Heart Failure Peripheral Vascular Disease Deep Vein Thrombosis and Pulmonary Embolism Valvular Diseases Percardial Disease Cerebrovascular Accident PHARMACOLOGY OF DRUGS USED IN CARDIOVASCULAR DISEASES  HYPERTENSION Hypertension, defined as a persistent systolic blood pressure (SBP) of greater than 150 mm Hg and/or a diastolic blood pressure (DBP),greater than 90 mm Hg for patients 60 years of age or older and an SBP greater than 140 and/or DBP greater than 90 for patients younger than 60 years of age and those who have chronic kidney disease or diabetes – (JNC 8). Hypertension affects approximately 1 billion people worldwide, designating it as the most common disease state. Hypertension is a major risk factor for cardiovascular diseases (CVD) and death resulting from cardiovascular causes. It is the most important risk factor for stroke and heart failure, Also a major risk factor for renal failure and peripheral vascular disease. HYPERTENSION-A KEY RISK IN CARDIOVASCULAR EVENTS The relationship between BP and risk of CVD events is continuous, consistent, and independent of other risk factors. Hypertension increases an individual's risk of various cardiovascular consequences approximately two to three times. HPT is implicated in 35 % of all atherosclerotic cardiovascular events & 49 % of all cases of heart failure Control of HPT reduces the risk of stroke, CAD, CHF, CKD, PVD, and mortality. Risk of developing these complications is continuous, starting at a blood pressure (BP) level as low as 115/75 mm Hg. GUIDELINES FOR MANAGEMENT OF HPT JNC 9 - 2023 AHA/ACC – 2017 ESH – 2023 National Guidelines for the Management of Cardiovascular Diseases - 2019 MANAGEMENT OF HYPERTENTION - GENERAL CONSIDERATIONS Establish the diagnosis of hypertension Assess for risk factors Assess for co-morbidities Set targets for BP control as well as monitoring parameters Advice on non-pharmacological therapies for BP control Counsel on adherence to pharmacological therapy Regular monitoring for efficacy and toxicity – routine follow- ups  Recommended life modifying activities and their effects on BP Modification Recommendation Approximate SBP reduction Weight reduction Maintain normal body weight (BMI 18.5- 2-20 mmHg/10Kg 24.9Kg/m2) Adopt DASH eating plan Consume a diet rich in fruits, vegetables 8-14mmHg and low fat dairy products with reduced content of saturated and total fat Dietary sodium Reduce dietary sodium intake to no more 2-8mmHg reduction than 100mmol per day(2.4g sodium or 6g sodium chloride Physical activity Engage in regular aerobic physical activity 4-9mmHg such as brisk walking(at least 30 min per day, most days of the week) Moderation of alcohol Limit consumption of no more than 2 drinks 2-4mmHg consumption per day in most men and to no more than 1 drink per day in women and lighter weight persons ANTIHYPERTENSIVES PRINCIPLES OF THERAPY Drug therapy for hypertension must be individualized. Important considerations in planning drug therapy are Co-existing medical problems and What impact the drug therapy will have on the patient's quality of life. Demographic factors Cultural implications Ease of medication administration (e.g., a once-a-day dosing schedule or transdermal administration) Cost CATEGORIES OF ANTIHYPERTENSIVES There are essentially seven main categories of pharmacologic drugs used to treat hypertension: Diuretics Adrenergic drugs (Alpha and Beta blockers) Vasodilators Angiotensin-converting enzyme (ACE) inhibitors, Angiotensin receptor blockers (ARBs) Calcium channel blockers (CCBs) Direct renin inhibitors. BETA BLOCKERS (BB) They block the sympathetic action of Noradrenaline and adrenaline at beta-adrenergic receptors located in the cardiac conduction system, myocardium, throughout the circulatory system and in the kidneys. As a result, they inhibit sympathetic stimulation of heart rate and myocardial contractility. They exhibit negative ionotropy, chronotropy, dromotropy, bathmotropy and lusitropy. Beta blockers lower blood pressure by lowering sympathetic tone and reducing circulating renin levels. Beta receptors exist in three distinct forms: beta-1 (B1), beta- 2 (B2), and beta-3 (B3). Classification Of Beta Blockers Classification is according to the 1. Selective nature of receptors they act on 2. Generation 3. Lipophilicity SELECTIVITY Divided into SELECTIVE BETA-1 and NON-SELECTIVE There are also beta-blocking drugs that affect both beta- 2 and/or beta-3 selectively; neither has a known clinical purpose to date Others have Alpha blocking activities NON-SELECTIVE BETA-1 SELECTIVE Propranolol Atenolol Carvedilol Bisoprolol Sotalol Metoprolol Labetalol Esmolol Timolol Acebutolol pindolol Classification of BB with examples CLASSIFICATION cont… GENERATIONS There are 3 generations of Beta blockers First generation E.g. Propranolol, Sotalol, Timolol, Nadolol nonselective: block β1 and β2 receptors. Second-generation agents E.g. Atenolol, Bisoprolol, Celiprolol, Metoprolol Cardio-selective agents Block β1-receptors in low doses, block β2-receptors in higher doses. More suitable in chronic lung disease or insulin-requiring diabetes mellitus Bisoprolol most selective Third generation agents E.g. Nebivolol (selective) , Carvidolol (non-selective) and Labetolol (non-selective) Vasodilatory properties mediated either by nitric oxide release (Nebivolol or Carvedilol) or by alpha-adrenergic blockade (Labetolol and Carvedilol) Classification based on Lipophilicity ❑Agents with low Lipophilicity (Hydrophilic) E.g. Atenolol, Sotalol, Esmolol, Nadolol They do not cause Nightmare/Hallucinations and Depression ❑Lipophilic Agents E.g. Propranolol, Metoprolol, Timolol, Nebivolol, Bisoprolol, Carvedilol Cause Nightmare/Hallucinations and Depression Should be avoided in Patients with Psychiatric Disorders or having sleep disturbance Indications Hypertension Heart failure : when patient is stable Post- MI secondary prevention Angina Atrial fibrillation Hyperthyroidism Portal Hypertension Aortic dissection Glaucoma Migraine prophylaxis Caution and Contraindications Asthma or history of bronchospasm – use minimally tolerated dose of Cardio-selective drug DM Second or third degree Heart block - Contraindicated BETA BLOCKERS SIDE EFFECTS Bradycardia with reflex tachycardia Postural and post-exercise hypotension Dry mouth Drowsiness Depression Edema Constipation Sexual dysfunction (impotence) NURSING CONSIDERATIONS Beta-blockers are a broad class of medications that are used for various clinical benefits but also carry the potential for adverse effects. Always monitor HEART RATE or PULSE when administering a beta- blocker. If pulse falls below 60 bpm (BRADYCARDIA) report Beta blockers may cause ORTHOSTATIC HYPOTENSION – monitor esp. 1st dose Do not stop beta blockers abruptly. Gradually tapper till discontinuation. - WHY? Asthmatics stand a high risk of Broncho-constriction. – WHY? Recommendation: Use an alternative antihypertensive or a cardio-selective drug Diabetics stand a risk of hypoglycemia with the use of beta-blockers. Recommendation: Use an alternative medicine or a cardio-selective drug ALPHA-2 ADRENERGIC RECEPTOR STIMULATORS (AGONISTS) E.g: Clonodine, Methyldopa These drugs are not typically prescribed as first-line antihypertensive drugs. because their use is associated with a high incidence of unwanted adverse effects such as orthostatic hypotension, fatigue and dizziness. They may be used as adjunct drugs in the treatment of hypertension after other drugs have failed or may be used in conjunction with other antihypertensive such as diuretics. Methyldopa is commonly used to treat hypertension in pregnancy. Clonidine is used primarily for its ability to decrease blood pressure. Must not be discontinued abruptly to prevent severe rebound hypertension. ALPHA-2 ADRENERGIC RECEPTOR STIMULATORS (AGONISTS) MECH. OF ACTION Act Centrally to decrease the adrenergic outflow by alpha-2 agonistic action from the central nervous system, leading to reduced total peripheral resistance and decreased systemic blood pressure. Alpha-2 agonistic activity does not affect cardiac output or renal blood flow.; hence, this drug is useful in hypertensive patients with renal insufficiency  INDICATIONS Hypertension CONTRAINDICATIONS Depression Pheochromocytoma WHY? Active hepatic disease Liver disorders due to previous therapy Significant drug history of MAO inhibitor therapy – WHY? Known hypersensitivity to methyldopa in any form ADVERSE EFFECTS Common adverse effects include: Nausea Rare yet clinically fatal adverse effects include Diarrhea Hemolytic anemia (Coombs positive) Headache Lupus-like syndrome Dizziness Myocarditis Sedation Pancreatitis Dry mouth Hepatotoxicity Rash Immune thrombocytopenia Reversible leukopenia Involuntary choreoathetosis movements Weight gain Rebound hypertension NURSING CONSIDERATIONS Methyldopa is useful in pregnancy because it has no teratogenic effects. – Ask clinician to switch to this alternative for women who are pregnant or trying to be pregnant Do not stop abruptly. Gradually tapper till discontinuation. - WHY? Excretion is slow in patients with renal failure, leading to the accumulation of the drug and its metabolites. After initiation of treatment, periodic testing of hemoglobin, hematocrit, and the red blood cell count is necessary to rule out hemolytic anemia Liver function tests are necessary for increased serum concentrations of alkaline phosphatase, aminotransferases, and bilirubin. Hepatic dysfunction may represent a hypersensitivity reaction. Therefore, a periodic assessment of hepatic function is important during the first 6 to 12 weeks of therapy. Abnormal liver function test results require discontinuation of the drug. The drug is contraindicated in active hepatic disease. ALPHA-1 BLOCKERS E.g. Alfuzosin, doxazosin, prazosin, tamsulosin and terazosin. They end with the suffix “-osin” They are classified as pregnancy category C drugs They are not used as first-line treatment drugs for hypertension unless there is a compelling indication like Prostate diseases Tamsulosin and Alfuzosin are not used to control blood pressure but indicated solely for symptomatic control of BPH. Doxazocin, prazosin and terazosin are a commonly used alpha-1 blocker for hypertension Prazosin is the prototypical alpha blocker but is not used as frequently as doxazosin (which has a long half-life and hence once daily dosing) ALPHA-1 BLOCKERS MECH. OF ACTION Alpha-1 blockers produce their pharmacological effects through alteration of the sympathetic nervous system in the vasculature. These drugs reduce peripheral vascular resistance and blood pressure by blocking alpha receptors, which are found in the walls of blood vessels, dilating both arterial and venous blood vessels. At present, however, the alpha-1 adrenergic antagonists are recommended only as adjunctive therapy of hypertension and not as monotherapy There are 3 Alpha-1 receptors, Alpha-1a and Alpha-1b. Alpha 1d. Alpha 1a is largely expressed in the prostate whiles Alpha 1b is found on the vascular smooth muscles. Because the nonselective alpha-1 adrenergic antagonists cause a relaxation of smooth muscle both in arterioles (alpha-1b receptors) and in the bladder neck and prostate (alpha-1a receptors), they are also useful in the therapy of symptoms of urinary obstruction due to benign prostatic hypertrophy. CONTRAINDICATIONS Hypersensitivity Caution in elderly and those with those prior to cataract surgery – WHY? ADVERSE EFFECTS Hypotension Weakness Tachycardia Tremulousness 1st dose hypotension Syncope Dizziness Headache NURSING CONSIDERATIONS Postural hypotension is particularly common after the initial dose of the alpha-1 adrenergic antagonist – MONITOR First-dose hypotension, syncope, dizziness, and headache due to vasodilation and vascular smooth muscle relaxation. Reflex tachycardia may occur due to a sudden decrease in blood pressure. These adverse effects tend to occur more often in the elderly and increase the risk of falls. To best avoid these adverse effects, the patient should take the medication at night It may take 4 to 6 weeks for the drug to achieve its full therapeutic effects. Educate the patient about this delayed onset of action and the bedtime dosing to avoid injury. ANGIOTENSIN- CONVERTING ENZYME INHIBITORS(ACEIs) E.g: Captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril. They are safe and efficacious and are often used as first line drugs in the treatment of both heart failure and hypertension. All ACE inhibitors have detrimental effects on the unborn fetus and neonate. ACE inhibitors are best avoided by pregnant women and used only if there are no safer alternatives. They are similar to one another but and differ in only a few chemical properties and some differences in their chemical properties. Captopril and lisinopril are the only two ACE inhibitors that are not prodrugs. Enalapril is the only ACE inhibitor that is available in a parenteral preparation FURTHER READING ACEIs have varying half lives. Read on the classification of ACEIs based on their half-lives. ACEIs Mechanism of action and Drug Effects These drugs (ACEIs) inhibit the angiotensin converting enzyme, which is responsible for the conversion of Angiotensin 1 formed through the action of renin to angiotensin 2. Angiotensin 2 is a potent vasoconstrictor and induces aldosterone secretion by the adrenal glands. Aldosterone stimulates sodium and water resorption, which can raise blood pressure. By inhibiting these processes, blood pressure is lowered. ACEIs NB: ACEIs block the breakdown of bradykinins and substance P, which accumulate and may cause adverse effects such as cough but might also contribute to the drugs antihypertensive, cardiac and nephroprotective effects. Indications of ACEIs Therapeutic effects of these drugs are related to their potent cardiovascular effects. Treatment of hypertension Treatment of heart failure Treatment of Myocardial infarction with left ventricular dysfunction and STEMI Reduction of proteinuria in Chronic Kidney disease Prevention of proteinuria in Diabetes Mellitus Treatment of Coronary artery disease Treatment of scleroderma renal crisis  They are considered the drugs of choice for hypertensive patients with heart failure. ACE inhibitors have a protective effect on the kidneys, because they reduce glomerular filtration pressure, hence the cardiovascular drug of choice for diabetics. ✓ACEIs have been shown by studies to reduce proteinuria hence recommended to prevent progression of diabetic nephropathy. CONTRAINDICATIONS Known allergy such as angioedema (laryngeal swelling) to ACEIs High serum potassium Pregnancy, Lactating mothers, children Patients with bilateral renal stenosis. Acute Kidney Injury Hypovolemia NB: The use of NSAIDs and ACE inhibitors may also predispose patients to the development of acute renal failure. Adverse Effects Fatigue Dizziness Mood changes Headaches Dry persistent irritating non-productive cough First dose hypotensive effect as a result of a significant decline in BP. Loss of taste Angioedema Renal impairment Hyperkalaemia Nursing Considerations If patient is on an ACEI and starts coughing, thorough investigation should be done to ascertain if its not an infective cough. If it is found to be induced by the ACEI, the drug can be changed to an ARB or another suitable antihypertensive. Hyperkalemia is a side effect of ACEIs. Potassium supplements and potassium-sparing diuretics, when administered with ACE inhibitors, may potentially result in hyperkalemia. Risk of hyperkalemia, esp. in patients with renal impairment or DM. Routine RFTs are essential to monitor serum Potassium. If Hyperkalemia results, drug needs to be temporarily stopped. LFTs are needed esp. if the patient is on an ACEI which is a prodrug e.g. Enalapril There is no significant benefit in the combined use of ACEIs and ARBs Patients on ACEIs who develop Acute Kidney Injury should have this medication discontinued because of increased risk of renal failure, hyperkalemia, hypotension, syncope and mortality. Monitor patients for Angioedema ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs) Angiotensin II receptor blockers (ARBs) are similar to ACEIs. E.g.s Losartan, Valsartan, Irbesartan, Candesartan, Olmesartan, Telmisartan. Mechanism of Action They block the binding of angiotensin II to type 1 angiotension II receptors. The ARBs affect primarily vascular smooth muscle and the adrenal gland by selectively blocking the binding of angiotensin II to the type 1 angiotensin II receptors in these tissues. ARBs block vasoconstriction and the secretion of aldosterone. Angiotensin II receptors have been found in other tissues throughout the body, but the effects of ARB blocking of these receptors is unknown. ARBs do not cause cough. ARBs are contraindicated in pregnancy (skull defects, oligohydramnios) ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs) Indications The therapeutic effects of ARBs are related to their potent vasodilating properties. Treatment of hypertension Treatment of heart failure Treatment of Myocardial infarction with left ventricular dysfunction and STEMI Reduction of proteinuria in Chronic Kidney disease Prevention of proteinuria in Diabetes Mellitus Treatment of Coronary artery disease Treatment of scleroderma renal crisis Contraindications Hypersensitivity to ARBs Hyperkalaemia Pregnancy Lactation Not to be prescribed together with ACEIs – WHY? ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs) Adverse Effects ▪ Chest pain ▪ Fatigue ▪ Hypoglycaemia ▪ Diarrhoea ▪ URTI ▪ Anaemia ▪ Hyperkalaemia ▪ Cough ▪ Myalgia, Arthralgia ▪ Back/Joint pain ▪ Angioedema (smaller %) Nursing Considerations ARBs serve as a suitable alternative for ACEI induced bradykinin cough ARBs are suitable substitutes for ACEIs is angioedema occurs from the ACEI Hyperkalemia is a side effect of ARBs. Caution with the use of Potassium supplements and Potassium sparing diuretics Risk of hyperkalemia, esp. in patients with renal impairment or DM. Routine RFTs are essential to monitor serum Potassium. If Hyperkalemia results, drug needs to be temporarily stopped. There is no significant benefit in the combined use of ACEIs and ARBs Patients on ARBs who develop Acute Kidney Injury should have their ARB medication discontinued because of increased risk of renal failure, hyperkalemia, hypotension, syncope and mortality. ASSIGNMENT Classify the ACEIs according to their half-lives and hence duration of action Classify the ARBs according to their half lives and hence possible duration of action Why are ACEIs and ARBs considered as renoprotective? Why is the use of ACEIs and ARBs contraindicated in Acute Kidney injury? CALCIUM CHANNEL BLOCKERS They are also known as CALCIUM CHANNEL ANTAGONISTS CLASSIFICATION: Two major categories: DIHYDROPYRIDINES and NON-DIHYDROPYRIDINES. The non-dihydropyridines include verapamil and diltiazem. The dihydropyridines include many other drugs, most of which end in “dipine“. Egs. Amlodipine, Barnidipine, Efodipine, Felodipine, Isradipine, Nifedipine, Nicardipine, Nimodipine, Nilvadipine, Pranidipine Mechanism of Action Calcium channel antagonists block the inward movement of calcium by binding to the L-type “long-acting” voltage-gated calcium channels in the heart, vascular smooth muscle, and pancreas. Their effectiveness in HPT management is their ability to cause smooth muscle relaxation by blocking the binding of calcium to its receptors, hence preventing contractions. There are two major categories of calcium channel antagonists based on their primary physiologic effects. The non-dihydropyridines have inhibitory effects on the SA and AV nodes, and myocardium resulting in a slowing of cardiac conduction and contractility. This allows for the reduction of Cardiac Output, reduces oxygen demand, and helps to control the rate in tachyarrhythmias. The dihydropyridines, in therapeutic dosing, have little direct effect on the myocardium, and instead, are more often peripheral vasodilators, which is why they are useful for hypertension, post-intracranial hemorrhage associated vasospasm, and migraines They also produce a relaxation of coronary vascular smooth muscle and coronary vasodilation; this increase myocardial oxygen delivery in patients with vasospastic angina. Nimodipine is more centrally acting and prevents cerebral artery spasms that can occur after a subarachnoid haemorrhage. CALCIUM CHANNEL BLOCKERS INDICATIONS Hypertension Coronary spasm Angina pectoris Supraventricular dysrhythmias Hypertrophic cardiomyopathy Pulmonary hypertension In addition to these, they are also prescribed for Raynaud phenomenon, subarachnoid hemorrhage, and migraine headaches CONTRAINDICATION known hypersensitivity Non-dihydropyridines are contraindicated in those with heart failure with reduced ejection fraction, second or third-degree AV blockade, and sick sinus syndrome because of the possibility of causing bradycardia and worsening cardiac output. Cardiogenic shock CALCIUM CHANNEL BLOCKERS Side Effects: Dizziness Flushing Palpitations Peripheral oedema Tachycardia Pulmonary oedema Gastrointestinal discomfort Muscular pains Drowsiness Vision disorders CALCIUM CHANNEL BLOCKERS NURSING CONSIDERATIONS Some of these formulations come as sustained release. Do not crush sustain release formulations Extended release formulations esp. Nifedipine contains lactose. Caution in use with patients with lactose intolerance Caution of its use in patients with heart failure, esp for the Non-dihydropyridines. Generally avoided in heart failure. Only Amlodipine is recommended for HFrEF. Nifedipine may be used in HFpEF DIURETICS Diuretics are drugs that accelerate the rate of urine formation via a variety of mechanisms. The result is the removal of sodium and water from the body Examples: Bendrofluazide, Hydrochlorothiazide, Indapamide, Frusemide, Bumetanide, Torasemide, Metolazone, Spironolactone, Eplerenone The diuretics are a highly effective class of antihypertensive drugs. They are listed as the first line antihypertensives for the treatment of hypertension. They may be used as monotherapy (single-drug therapy) or in combination with drugs of other antihypertensive classes The thiazide diuretics (e.g. hydrochlorothiazide, bendrofluazide, indapamide) are the most commonly used diuretics for treatment of hypertension. They primarily work in the kidney They are classified according to the portion of the NEPHRON where they act, their chemical structure, and their diuretic potency The Nephron and Diuretic Sites Action  Their primary therapeutic effect is by increasing loss of water through urine thereby decreasing the plasma and extracellular fluid volumes, which results in decreased preload. This leads to a decrease in cardiac output and total peripheral resistance, all of which decrease the workload of the heart. CLASSIFICATION Thiazide and thiazide-like Diuretics Loop Diuretics Potassium Sparing Diuretics The most potent diuretics are the loop diuretics Thiazides and thiazide-like diuretics are usually indicated as 1st line therapy for hypertension. Loops are only indicated when there is a compelling indication like in Heart failure and Chronic Kidney disease Potassium Sparing Diuretics are usually not indicated as 1st line therapy for Hypertension. But is usually indicated for Resistant Hypertension and Heart failure Mechanism of Action The hypotensive activity of diuretics is due to many different mechanisms. They cause direct arteriolar dilation, which decreases peripheral vascular resistance. They also reduce extracellular fluid volume, plasma volume, and cardiac output, which may account for the decrease in blood pressure THIAZIDES: these drugs block the Na/Cl channel in the distal convoluted tubule leading to the inhibition of Sodium and water LOOP: These drugs act primarily along the thick ascending limb of the loop of Henle, blocking the Na/K/2Cl channel. This leads to inhibition of the re- absorption of Na, K and Cl ions and Water. The reabsorption of Mg and Ca is also affected. POTASSIUM SPARING: work in the distal convoluted tubules AND collecting ducts, where they interfere with sodium-potassium exchange. Spironolactone and Eplerenone competitively binds to aldosterone receptors in the DCT and therefore blocks the resorption of sodium and. Amiloride and triamterene do not bind to aldosterone receptors. However, they inhibit both aldosterone-induced and basal sodium resorption, working in both the distal tubule and collecting ducts. SPECIFIC DIURETICS THIAZIDES AND THIAZIDE-LIKE DIAURETICS E.g. – Thiazides – Bendrofluazide, Chlorothiazide and Hydrochlorothiazide Thiazide-like: Chlorthalidone, Indapamide and Metolazone Among this class, the thiazide-like are preferred over the thiazides Chlorthalidone and Indapamide (thiazide-like) are more potent than the hydrochlorothiazide (thiazide) LOOP DIURETICS Loop diuretics (E.g. bumetanide, ethacrynic acid, furosemide, and torsemide) are very potent diuretics. Bumetanide, furosemide, and torsemide are chemically related to the sulfonamide antibiotics. Because they are structurally related to the sulfonamides, they are often listed as contraindicated in sulfa-allergic patients. INDICATIONS Essential Hypertention Heart Failure – loops Chronic Kidney Disease – loops Oedema Kidney stones Liver Disease – loops and aldosterone antagonists CONTRAINDICATIONS Electrolyte imbalance Hypotension Dehydration Oliguria/Anuria Azotemia Hepatic Encephalopathy Hepatic Coma DIURETICS ADVERSE EFFECTS Electrolyte imbalance Polyuria Hypotension Dizziness Dehydration Headache Hyperuricemia - gout Hyperglycaemia Impotence NURSING CONSIDERATIONS Diuretics cause excessive urination. Patients should therefore be advised to take them preferably in the mornings Daily weighing of patients is needed to indirectly measure diuretic action esp with loop diuretics. Diuretics may cause dehydration. This is largely due to the excessive urination caused by their action. Therefore strictly monitor fluid input and output chart for in-patients. Out-patients are also advised to ensure adequate hydration Routine laboratory investigations esp. RFTs should be requested and analyzed. In the event of electrolyte imbalance, report to clinician In-patients on diuretics esp. on loops can cause severe dehydration which can even lead to AKI (pre-renal). Monitor urine output as well as electrolytes Electrolyte imbalance esp. K and Na can lead to Cardiac and Neurological complications respectively VASODILATORS They act directly on arteriolar and or venous smooth muscle to cause relaxation. They do not work through adrenergic receptors. Examples: Minoxidil, hydralazine, diazoxide, nitroprusside. Mechanism of action Direct – acting vasodilators are useful as antihypertensive drugs because of their ability to directly cause peripheral vasodilation. This results in a reduction in systemic vascular resistance. Vasodilation produce significant hypotension. Diazoxide and hydralazine and minoxidil work primarily through arteriolar vasodilation, whereas nitroprusside has both arteriolar and venous effects. Indications Hypertension Hypertensive emergencies (Sodium nitroprusside, diazoxide) in which blood pressure is severely elevated. Contraindications Known drug allergy Hypotension Cerebral oedema Head injury Acute MI Coronary artery disease. Heart failure secondary to diastolic dysfunction. DIRECT RENIN INHIBITOR Aliskiren is the only drug in this class. Mechanism of Action: acts as a renin inhibitor, which blocks the conversion of angiotensinogen to angiotension I Used alone or in combination with other antihypertensives like diuretics (usually thiazides) or an ARB SIDE EFFECTS Lightheadedness Difficulty in breathing Itching CONTRAINDICATIONS Loss of bladder control Hypersensitivity Cough Pregnancy Dizziness Diabetics on an ACEI or ARB Rapid weight gain Muscle pain General Nursing Considerations in Anti-hypertensives Nursing interventions may help patients achieve stable blood pressure while minimizing adverse effects during treatment with antihypertensives. Many patients have problems complying with treatment because the disease itself is silent or without symptoms. Because of this, some patients are unaware of their increased blood pressure or think that if they do not feel bad there is nothing wrong with them, which poses many problems for treatment. Also, the antihypertensives are often associated with multiple adverse effects hat may impact patients’ energy level, self-concept, and/or sexual integrity. These adverse effects may lead patients to abruptly stop taking the medication. Inform patients that any abrupt withdrawal is a serious concern because of the risk for developing rebound hypertension, which is a sudden and very high elevation of blood pressure. This places the patient at risk for a cerebrovascular accident (STROKE) or other cerebral or cardiac adverse events like Heart Failure, Myocardial Infarction (Heart Attack) Let clients understand the condition and hence the need for life long therapy. Management of Hypotension HYPOTENSION Hypotension is a decrease in systemic blood pressure below the levels that can support tissue perfusion. Usually, BPs below 90/60 mmHg or MAP below 65 mmHg are recognized as hypotensive Hypotension is sometimes asymptomatic It only becomes a concern once pumping pressure is inadequate to perfuse key organs with oxygenated blood It is considered as ORTHOSTATIC when there is a decrease in ≥ 20/10 mmHg on positional change from lying to standing Severe hypotension can lead to SHOCK HYPOTENSION Hypotension may occur as a result of Low Cardiac Output Low Total Peripheral Resistance Or Both Both CO and TPR function as feedback compensation mechanisms. Hypotension results when this feedback mechanism is overwhelmed. Acute disease processes of hypotension is termed as SHOCK  Shock designates a sudden disturbance of mental equilibrium. However , it may be more explicitly defined as a profound haemodynamic, and metabolic disturbance due to failure of the circulatory system to maintain adequate perfusion of the vital organs of the human body. The type of shock is determined by the etiology: TYPES OF SHOCK 1. Distributive 2. Cardiogenic 3. Hypovolemic 4. Obstructive 5. Combined-type TYPES OF SHOCK CARDIOGENIC SHOCK : Designates the shock resulting from inadequate cardiac function. Thus it’s a failure to achieve sufficient cardiac output with maintained total peripheral resistance Patients experiencing this type of shock classically present with cool, dry extremities and skin with bradycardia ✓For instance Myocardial infarction, or mechanical obstruction which is characterized by hypovolemia, hypotension, cold skin, weak pulse and confusion. DISTRIBUTIVE SHOCK This occurs when the body fails to maintain total peripheral resistance with maintained cardiac function attempting to compensate This classically presents with warm extremities and skin, oedema, increased mucous secretion, and tachycardia Classically associated with ANAPHYLACTIC ALLERGIC REACTIONS and SEPTIC SHOCK Septic Shock: designates shock due to an infective process TYPES OF SHOCK HYPOVOLAEMIC SHOCK: designates the shock due to insufficient blood volume either from severe haemorrhage or other loss of body fluid or from wide spread vasodilation so that normal blood volume cannot maintain tissue perfusion viz, the symptoms very much resemble to those of cardiogenic shock above. This is possible through trauma, overuse of diuretics, severe diarrhoea or vomiting Cortisol deficiency as seen in Addison disease – excessive uresis Sheehans syndrome TYPES OF SHOCK OBSTRUCTIVE SHOCK Occurs with obstruction, constriction or compression of the cardiovascular system such that blood flow does not efficiently occur. This leads to a relative drop in blood pressure May occur secondary to Pulmonary Embolism, tension pNeumothorax, cardiac tamponade, constrictive pericarditis or some restrictive cardiomyopathy  Shock is an absolute medical emergency characterized by inadequate perfusion of certain vital and important organs in a human body. Invariably caused due to an extremely low profile in the arterial BP. ❖Treatment of shock essentially focuses on three vital aspects, namely: ✓To restore precisely the level of tissue perfusion ✓To reinstate the desired intravascular blood volume, and ✓Treat underlying cause ASSIGNMENT Discuss the various drugs used in the management of Hypotension. Indicate which type of shock each drug is used for