PCC2 Cardiovascular System - Hypertension

Hypertension Elevated arterial blood pressure above the expected range: 140/90 - 160/95 mmHg borderline How does an increase in sympathetic activity affect BP ? Small increases in sympathetic activity will increase cardiac output and peripheral resistance, increasing BP. Primary (essential) Hypertension Cause unknown 90% of hypertension cases Secondary hypertension Known cause - e.g., Kidney or Endocrine diseases What factors are associated with Hypertension ? - Reduced life expectancy - Left ventricular wall thickening - Atheroma - Coronary heart disease - Stroke - Peripheral vascular disease - Genetic disposition (family history) - Ageing = blood vessels lose flexibility as we older and this can contribute to an increase in blood pressure. - Gender Hypertension risk factors - Lack of exercise - Poor diet = one that is high in salt - Obesity - Regularly drinking too much alcohol Smoking and stress can contribute to the risk of developing hypertension. 1 / 22 - Men up to the age of 45yrs are more likely to have hypertension than women of the same age Hypertension risk factors - Gender - 45-64 yrs the risk of hypertension is the same for men and women - From 65yrs women are more likely to have hypertension Arteriosclerosis A process involving symmetrical thickening of the muscular medial layer of the walls of arteries throughout the body. - arises in response to hypertension - can be reversed to an extent with treatment - also associated with ageing Peripheral resistance - this further exacerbates the problem and eventually results in fibrosis and calWhat problem arises as a result of artecification riosclerosis ? - commonly known as hardening of the arteries, but its is not the same as atherosclerosis. 1. Reductions in: - body weight - salt and alcohol consumption 2. Smoking cessation Starting points for Hypertension treatment ? 2 / 22 Step 1 - Asian or Caucasian under 55yrs - drugs affecting the renin angiotensin system are a good first choice (ACE inhibitor) / Asian or Caucasian 55 years or over or Afro-Caribbean of any age - calcium channel blocker is a good starting point Step 2 - Combination of one drug from each group when a patient's Hypertension worsens NICE stepped treatment guidelines for Step 3 - 'triple therapy', where three hypertension ? drugs are used to control a patient's Hypertension Step 4 - If triple therapy is not sufficient, other agents e.g., spironolactone etc. may be used. Classes of drugs that can lower BP - Vasodilators - B-blockers - Centrally acting drugs - Diuretics Examples of Vasodilator drugs ? - ACE inhibitors - ARA's (Angiotensin Receptor Antagonists/Blockers) - Calcium channel blockers - alpha 1-adrenoceptor antagonists - Hydralazine - Minoxidil 3 / 22 Vasodilating drugs MOA - Lower blood pressure by causing vasodilation - Reduces peripheral resistance = less pressure is required to pump blood around the body. Renin-Angiotensin System (RAS) A physiological mechanism that tries to maintain BP and Na+ ion concentration, and therefore the perfusion rate of blood through the kidneys. Renin An enzyme that is released from the juxtaglomerular apparatus of nephrons in response to a falling Na+ ion concentration in distal convoluted tubules and falling renal perfusion pressure. - Renin acts on angiotensinogen - an inactive precursor always present in the blood, to form angiotensin I - As angiotensin I passes through the lungs, it is converted into angiotensin II by the enzyme ACE - Angiotensin II is a potent vasoconstrictHow does the Renin-Angiotensin Sys- ing octapeptide, which will therefore intem maintain BP and Na+ ion concentra- crease blood pressure tion ? - Angiotensin II also causes aldosterone to be released by the adrenal glands (a mineralocorticoid that increases renal Na+ ion reabsorption) - There is now more water being retained, this extra water increases the volume of blood, which therefore increases blood pressure. 4 / 22 What happens when the Renin-Angiotensin System is inappropriately active ? - Can cause hypertension Can be reversed if: - angiotensin II production is inhibited - blood pressure will then fall ACE inhibitors which reduce the production of angiotensin II - Captopril - Enalapril - Lisinopril - Ramipril What vessels do ACE inhibitors affect ? - Capacitance - Resistance Side effects caused by ACE inhibitors ? - First dose hypotension - Dry cough - Angioedema ACE inhibitor side effects - First dose hypotension counselling points - Patients are advised to take any initial dose just before they go to bed - This means if their BP drops, they will be lying down/asleep anyway - Less likely to experience problems such as dizziness ACE inhibitor side effects - Dry cough pathophysiology - Bradykinin accumulation = a peptide produced in the body that can cause vasodilatation, signs and symptoms of inflammation and pain. (normally broken down by kinases which is similar to ACE) - ACE inhibitor inhibits the breakdown of bradykinin 5 / 22 - Bradykinin accumulates around the lungs = causes a persistent dry cough - Rare, potentially serious side effect - due to bradykinin accumulation ACE inhibitor side effects - Angioedema ACE inhibitors Cautions and ContraindiPotassium levels may have to be meacations: Co-administration with potassisured in order to avoid hyperkalaemia. um sparing diuretics Renal failure may occur due to a lowered afferent arteriolar tone reducing glomerular filtration. ACE inhibitors Cautions and Contraindications: Bilateral renovascular disease Should be avoided ! - unless essential - Drugs may adversely affect foetal blood ACE inhibitors Cautions and Contraindi- pressure and renal function. cations: Pregnancy - Reduced amounts of amniotic fluids and skull defects in the neonate have also been reported. - Potassium levels and renal function tests (urea and creatine) should be monitored. ACE inhibitors - Monitoring - Patients should be counselled about the risk of first dose hypotension and to report a persistent dry cough. - Affects the Renin-Angiotensin System by antagonising AT1 receptors e.g., Losartan, Valsartan, Candesartan - Angiotensin is still being produced, but it can't bind to the receptor it needs as its Angiotensin Receptor Antagonist/ Blockblocked ers (ARAs or ARBs) - MOA - BP will fall - ARAs do not affect kininases = bradykinin can still be broken down 6 / 22 - These drugs therefore do not produce a dry cough They are: - effective - less expensive - many patients are able to tolerate their side effects Why are ACE inhibitors used before ARAs ? ARAs are used after ACE inhibitors have been tried and found to cause problems. - Orthostatic hypotension - Dizziness - Headache - Fatigue - Hyperkalaemia - Rash Angiotensin Receptor Antagonist/ Blockers - Side effects - Renal artery stenosis - Pregnancy Angiotensin Receptor Antagonist/ Block- - Breastfeeding ers - Cautions and Contraindications - Aortic stenosis - Potassium sparing diuretics (monitor k+ ion concentration) - Increased sympathetic tone results in vascular ±1adrenoceptor activation - This stimulates phospholipase C = results in the production of the second messenger inositol triphosphate How does vascular smooth muscle tone result in an increase in BP ? - Inositol triphosphate triggers Ca2+ ion release from sarcoplasmic reticulum stores - Ca2+ ions now bind to calmodulin = activates a kinase to phosphorylate myosin light chain (MLC) 7 / 22 - This enables myosin and actin filaments to interact - Resulting in smooth muscle contraction and a vasoconstriction that will increase BP In addition to this: - Voltage operated L-type Ca2+ ion channels open in the membranes of vascular smooth muscle cells - causes more Ca2+ ions to enter = further increases the vascular tone e.g., Nifedipine - block Voltage operated L-type Ca2+ channels - this reduces the number of free cytoHow do Ca2+ channel blockers lower BP plasmic Ca2+ ions ? - fewer Ca2+ ions can interact with calmodulin = reduces vascular tone - this causes peripheral resistance to decrease = lowers BP Dihydropyridine type Ca2+ channel blockers e.g., Nifedipine, Felodipine and Amlodipine - They selectively affect vascular channels - Can cause a generalised arterial vasodilation - Have no cardiac actions Dosing for Felodipine and Amlodipine They have longer durations of action so they can be administered once daily. - Selectively affect cardiac L-type channels Why is Verapamil and Diltiazem useful - Slow down SA and AV node conduction for ischaemic heart disease (e.g., angi= slowing heart rate na, conduction disorders) ? - This shortens the plateau for cardiac muscle cell action potentials and exhibit8 / 22 ing a negative inotropic and chronotropic effect How do the effects of Diltiazem and Verapamil vary ? Diltiazem: - tends to have an intermediate effect - acts on both peripheral arteries and the heart = can be used to reduce BP Verapamil: - more useful for its predominant effects on the heart - mostly used for arrhythmias or angina - Hypotension - Peripheral oedema Nifedipine and Amlodipine side effects Hypotension (can be caused if blood vessels dilate too much) = leads to Nifedipine and Amlodipine side effects - headaches, dizziness and flushing Hypotension - This hypotension will also cause a reflex tachycardia as the heart tries to beat faster in order to increase BP. - Arteries dilate more than veins - Arteries now carry a larger volume of Nifedipine and Amlodipine side effects - blood Peripheral Oedema - Since the carrying capacity of veins has not increased much, fluid may leak out into tissues from capillary beds. Verapamil and Diltiazem - side effects Verapamil and Diltiazem side effects Hypotension - Hypotension - Constipation (commonly occurs when verapamil is used) - Due to a direct action on the heart caused by reduced Ca2+ ion conductance - Results in a bradycardia, signs of heart block and congestive heart failure may be precipitated or exacerbated. 9 / 22 - Acts on cerebral arteries Nimodipine - Used in the prevention and treatment of vascular spasm which can occur after a sub-arachnoid haemorrhage in the brain. - Antibacterials - Antifungals - Anticonvulsants - Statins - Theophylline - Grapefruit juice Things Calcium channel blockers commonly interact with that lead to the drug being metabolised by hepatic Cytochrome P enzymes ? Due to the risk of bradycardia and heart Use of B-blockers and Calcium channel block, B-blockers should be used exblockers ? tremely cautiously with diltiazem and avoided with verapamil ! e.g., Prazosin, Doxazosin - Administered orally ±1Adrenoceptor Antagonist - Inhibit ±1adrenoceptor mediated vasoconstriction by antagonising vascular ±1-adrenoceptors Results in: - Vasodilation - Reduced peripheral resistance - Fall in BP ±1Adrenoceptor Antagonist - MOA ±1Adrenoceptor Antagonist - Main side effects Postural hypotension = due to an impaired arteriolar vasoconstriction reflex upon standing up. - Blood delivery to the brain can be temporarily impaired as it may pool in the low portion of the body. - Reduce bladder and Prostate resistance - Increase urinary flow How do ±1Adrenoceptor Antagonists improve symptoms of prostatism ? Slightly improves blood lipid profile by lowering levels of: 10 / 22 How does Doxazosin affect blood lipid profiles ? - LDL cholesterol - VLDL - Triglyceride but it raises HDL levels Hydralazine - Reserved for hypertension that is resistant to other treatments - Administered orally or intravenously Hydralazine MOA Works by an unknown mechanism - it may interfere with vascular smooth muscle inositol trisphosphate - this reduces vascular resistance and BP Hydralazine - Side effects - Reflex tachycardia - Angina provocation - Headaches - Fluid retention - Idiopathic systemic lupus - Erythematosus Minoxidil - Potent vasodilator - Only used for hypertension that is resistant to other drugs - Administered Orally - Due to hirsutism effect = topical minoxidil lotions are available for treating androgenic alopecia. - Opens vascular smooth muscle K+ ATP channels = causes hyperpolarisation Minoxidil MOA - Affected smooth muscle cells now find it harder to depolarise = reduces Ca2+ ion entry through L-type channels - This causes a reduced smooth muscle tone and a vasodilation - Hirsutism - Na+ and H20 retention Minoxidil - Side effects 11 / 22 - Tachycardia - Cardiotoxicity - Used to be first line treatment for hypertension = now been found that ACE inhibitors or calcium channel blockers used in combination with diuretics etc. Beta-Adrenoceptor Antagonist (²-blockare more effective treatments. ers) - Oral and Intravenous drugs - Introduced in the 1960s - They are still used for treating patients with resistant hypertension Centres around the fact that cardiac output (CO) is determined by heart rate (HR) and stroke volume (SV) CO = HR x SV ²-Blockers acute MOA - antagonising ²1-adrenoceptor prevents it from being activated by the sympathetic division of the autonomic nervous system - results in a decrease in heart rate, hence cardiac output falls = BP will be lowered Over time cardiac output recovers in ²-Blocked patients, BP still remains low due to a unknown mechanism that may cause: ²-Blockers chronic MOA - Peripheral vascular resistance to be 'reset' at a lower level - Reduced renal renin release - Reduced sympathetic outflow from the CNS e.g., Propranolol - capable of producing wide spread ²1and ²2-blockade. 12 / 22 Non-selective ²-Blockers e.g., Atenolol, Bisoprolol and Metoprolol - more selective for ²1-adrenoceptors Cardioselective ²-Blockers Carvedilol Solubility of ²-Blockers Capable of producing both a non-selective ²and ±1blockade. - Metoprolol and Propranolol = more lipid soluble, can penetrate the blood brain barrier more readily - Atenolol, Celiprolol, Nadolol = more water soluble - Both drugs have identical right hand halves, but the left hand half of the molecules are different - Amide group (Atenolol) = responsible for significantly increasing its water solubility Structure activity relationship (SAR) of Atenolol and Propranolol - Right hand sides = responsible for the binding of the drug to the ²-adrenoceptors - Left hand sides = play a role in making propranolol a non-selective ²-blocker, and atenolol a ²1-selective blocker. - Bronchospasm - Fatigue 13 / 22 - Cold extremities Beta-Adrenoceptor Antagonists (²-Blockers) - Side effects - Sleep disturbances - Male impotence - Bradycardia and cardiac depression - Insignificant increases in airway resistance can be serious for asthmatics who are affected by reversible bronchospasm = B-Blocker drugs should be avoided ! ²-Blockers side effects - Bronchospasm ²-Blockers side effects - Fatigue - B-Blockers can be used cautiously, together with lung function monitoring, in patients with severe obstructive lung diseases Cardioselective agents should be preferred - e.g., Metoprolol Likely to be caused by reduced Cardiac output and reduced muscle perfusion. Loss of ²-adrenoceptor mediated vasodi²-Blockers side effects - Cold extremities lation, but still occurs with Cardioselective blockers. ²-Blockers side effects - Sleep disturbances More lipid-soluble ²-Blockers can pass through the blood-brain barrier, causing bad dreams. - Depression may also occur in patients taking ²-Blockers Centrally mediated rather than a peripheral effect as problem is more com²-Blockers side effects - Male impotence mon with lipid-soluble ²-Blockers passing through the blood-brain barrier. - Signs of heart failure may develop in ²-Blockers side effects - Bradycardia and elderly patients cardiac depression - Heart block can occur in patients being 14 / 22 treated with antiarrhythmic drugs that impair cardiac conduction - Asthmatics - Hypoglycaemia - Calcium channel blockers - Peripheral vascular disease ²-Blockers Cautions & Contraindications - Non-selective ²-Blockers should not be given to asthmatics = triggers severe bronchoconstriction and interfere with ²-Blockers Cautions & Contraindications - the actions of drugs such as salbutamol Asthmatics - Caution is still required with cardioselective ²-Blockers, as they lose selectivity at higher doses - Glucose is released in response to adrenaline and the symptom of tachycardia gives diabetic patients an urgent warning to consume carbohydrates - ²-Blockers blunt this response = hypoglycaemia is likely to go unnoticed ²-Blockers Cautions & Contraindications - Cardioselective ²-Blockers may be better Hypoglycaemia = hepatic glucose release is mediated by ²2-adrenoceptors - ²-Blockers also impair glycaemic control by affecting carbohydrate metabolism, providing another reason why they should preferably be avoided in patients with diabetes mellitus - ²-blockers may worsen PVD by a combination of decreased cardiac output and ²-Blockers Cautions & Contraindications - unopposed alpha (±)adrenergic drive Peripheral vascular disease (PVD) (vascular ²-receptors tend to cause a vasodilation, whereas vascular ±receptors tend to cause a vasoconstriction) 15 / 22 - Centrally acting ±2adrenoceptor agonists - They also reduce HR and CO - Methyldopa can be used to treat Hypertension during pregnancy Centrally acting drugs - Methyldopa = oral Examples of Centrally Acting Drugs ? - Clonidine = oral and intravenous - Moxonidine = oral - Stimulates presynaptic ±2adrenoceptors in the vasomotor centre of the medulla oblongata - This reduces noradrenaline release - Sympathetic outflow is reduced causing a vasodilation Centrally Acting Drugs - MOA These drugs also reduce HR and CO Centrally Acting Drugs - Side effects Orthostatic hypotension Diuretics - Increase the volume of urine produced, so there is an increase the amount of water excreted - The water will have originated from the blood, so that circulatory volume will decrease Therefore diuretics can be used to treat a range of cardiovascular disease e.g.,: - hypertension - heart failure - oedema - renal disease - glaucoma How much circulating blood does the venous system contain ? 75% Why are veins thought of as capacitance - They are stretchy and compliant vessels ? - Can accommodate large changes in 16 / 22 blood volume, be that through loss or expansion When does oedema occur ? When large volumes of blood accumulate in the veins Often due to conditions such as: - heart failure = blood is not effectively returning to or being pumped by the heart - renal or liver failure = when the body fails to eliminate or handle fluid effectively Role of valves in the veins Prevent the backward flow of blood Skeletal muscle pump Body relies on movement via this pump to return blood to the heart in a forwards direction. - The body relies on the skeletal muscle pump to return blood to the heart in a forwards direction - Gravity can cause pooling of blood in the vein e.g., If a person stands still without movDescribe how symptoms of oedema can ing the skeletal muscles form ? - Blood will accumulate in the large veins in the legs - Over time water diffuses from distended veins by osmosis into the surrounding tissues resulting in the symptoms of oedema Thiazides and Thiazide-like diuretics - Moderately potent diuretics - Duration of action = 12-24hrs - Usually administered at the start of the day to avoid sleep interference caused by diuresis Examples of Thiazide drugs ? - Bendroflumethiazide - Cyclopenthiazide 17 / 22 Examples of Thiazide-like diuretic drugs ? - Indapamide - Chlortalidone - Inhibit Na2+ ion reabsorption from the initial segment of distal convoluted tubules - NaCl reabsorption is blocked by thiazides inhibiting the apical (luminal) symporter - More NaCl remains in the filtrate = more water will be excreted (which is necessary to maintain an osmotic balance) Thiazides MOA Thiazides side effects - Chronically the arterial vasodilation caused by thiazides produces a hypotensive effect This may result from the reduced entry of Ca2+ ions into vascular smooth muscle (possibly as a consequence of Na+ ion depletion) Metabolic side effects: - Increased serum cholesterol levels - Impaired glucose tolerance - Hyperuricaemia - Hypokalaemia Due to this they are no longer used as first line agents on their own. 18 / 22 Why are Thiazides less potent when used for the treatment of mild chronic heart failure ? They work in the cortical diluting segment of the distal tubule where only 10% sodium reabsorption occurs. - Maximum diuresis occurs at low doses and does not increase with increasing Why are Thiazides described as 'low ceil- dosage ing' agents ? - They are also ineffective in moderate to severe renal impairment Loop diuretics - Work in a similar way to thiazides - Very potent - Can be administered orally, intramuscularly and intravenously - Mostly used to control oedematous symptoms e.g., those occurring in heart failure (e.g., Furosemide) - Can be used to reduce peripheral and pulmonary oedema in moderate and severe heart failure cases - Can be used in some circumstances in renal failure - They are not routinely used in the treatment of hypertension, can be used when a patient does not respond to thiazides Use of Loop diuretics intravenously ? - Can be used in emergencies since it produces a rapid effect. or - In patients with heart failure who develop congestion (build up of oedematous fluid) in the GI tract which impairs the absorption of orally administered drugs. They work on the ascending loop of henle, this segment has a very high capacity Why are Loop diuretics very potent drugs for reabsorbing salt, these diuretics are ? very potent and they produce a large diuresis. 19 / 22 They inhibit salt reabsorption in the thick ascending limb of the loop of Henle by inhibiting Na+/K+/2Cl- cotransport. Loop diuretics MOA Why are Loop diuretics called 'high ceil- Because the blockade of sodium reabing' diuretics? sorption continue as dose is increased. How can the Optimum dose response be achieved with Loop diuretics ? By dividing the dosages - Higher doses are required Loop diuretics use in patients with renal - They should not be administered too impairment ? quickly to prevent ototoxicity in these patients Loop diuretic side effects Metabolic side effects: - Hypokalaemia - Hyperuricaemia - Hyperglycaemia - Hypotension Loop diuretic Dose cautions Caution is needed with high doses, especially administered via IV = this may result in dehydration, electrolyte imbalances and deafness (resulting from altered electrolyte composition of the endolymph). - Severe hypokalaemia or hyponatraemia, anuria Loop diuretic contraindications - Caution is required with concomitant use with cardiac glycosides = due to risk of hypokalaemia potentiating the glycoside effects and causing potential toxicity. 20 / 22 - Weak diuretics that are not very effective agents when used alone e.g., Amiloride, Triamterene, Aldosterone receptor antagonists e.g., Spironolactone and Eplerenone Potassium Sparing Diuretics - For hypertension treatment these drugs have been traditionally combined with thiazide or loop diuretics in order to prevent hypokalaemia - They have also been used in the management of heart failure / Aldosterone antagonists are also used in the management of heart failure - Amiloride Examples of Potassium Sparing Diuret- - Triamterene ics ? - Aldosterone receptor antagonists e.g., Spironolactone and Eplerenone e.g., Spironolactone and Eplerenone Aldosterone receptor antagonist drugs Side effect - may cause gynaecomastia (breast enlargement in males) - Reduce the reabsorption of Na+ ions = leads to an increased excretion of K+ and H+ ions Loop and Thiazide MOA This is because the increased Na+ load in the latter part of the distal convoluted tubule and the collecting duct is unusual and the kidney will try to reabsorb it - Aldosterone stimulates the reabsorption of these Na+ ions - This generates a negative electropotential in the lumen of the nephrons = encourages K+ and H+ ion exchange/secretion 21 / 22 Potassium-Sparing Diuretics MOA Amiloride and Triamterene MOA Spironolactone and Eplerenone MOA Therefore hypokalaemia can be a side effect for loop and thiazide diuretics - Work by reducing Na+ ion reabsorption - This automatically reduces the need for K+ or H+ ion exchange - More K+ ions will be retained = prevents hypokalaemia Decrease luminal membrane permeability by blocking Na+ channels. Competitively antagonise aldosterone's cytoplasmic receptor. - Hyperkalaemia - Hyponatraemia Potassium Sparing Diuretics - Side ef- - GI tract disturbances fects Spironolactone and Eplerenone = may causse gynaecomastia (breast enlargement in males) - Use in combination with either ACE inhibitors or ARAs carry the risk of causing hyperkalaemia + should not be used with potassium supplements Potassium Sparing Diuretics - Cautions/Contraindications Why might combination products be used ? - This is due to ACE inhibitors + ARAs reducing aldosterone secretion The nephron is already being under stimulated by aldosterone and so potassium sparing diuretics will compound this effect. Compliance is an issue = this reduces the number of medications a patient has to take e.g., Co-amilofruse - contains amiloride (a potassium sparing diuretic) and furosemide (a loop diuretic). 22 / 22