Hypertension Pharmacotherapy PDF

Pharmacotherapy of Hypertension Course Name: Pharmacotherapy of CVS & Respiratory systems Course Code:PHD215  Learning Outcomes  At the end of this lecture, students should be able to: (CO1:PO1)  Understand the definition of hypertension and its association with cardiovascu...

Pharmacotherapy of Hypertension Course Name: Pharmacotherapy of CVS & Respiratory systems Course Code:PHD215  Learning Outcomes  At the end of this lecture, students should be able to: (CO1:PO1)  Understand the definition of hypertension and its association with cardiovascular disease.  Understand and explain the management of hypertension.  Identify drugs use to treat hypertension their mechanisms of action and adverse effects.  at t e Hypertension although but at the bottom is more thanstilConside t a ▪ ‘Hyper’ = high, ‘tension’ = pressure ▪ Hypertension=high blood pressurehypertension ▪ When the arterial pressure is greater than the upper range of accepted normal limit, this condition is called hypertension. Mean arterial pressure greater than 110mmHg Systolic blood pressure greater than 135- 140mmHg normal 12 %0 - Diastolic blood pressure greater than (Myog > Stage 2 90mmHg - ↳ the higher category should be selected.  What is Blood Pressure?  The pressure exerted by the blood on the walls of the blood vessels as it passes through it”. Normal BP:120/80 mmHg ◼ Systolic pressure:  “When the ventricles of the heart contract and eject blood, the pressure created in the arteries is called systolic pressure. Normal value:120 mmHg. ◼ Diastolic pressure:  “When the ventricles relax and the heart temporarily stops ejecting blood, pressure in the arteries will fall, this is called diastolic pressure. Normal value:80mmHg 16 70-59 90-99 10-139 -159 18 179 100-109 110  2J Types of hypertension Primary essential hypertension:  About 90% of hypertensive people  No underlying cause has been identified  Possible factors involved: diet, obesity, age, race, heredity, stress and smoking.  Cannot be cured completely, but most cases can be controlled by restricting salt, fat and cholesterol intake, losing weight, stopping smoking, managing stress and taking antihypertensive dugs. the blood Secondary hypertension: getdisease cause  About 10% of hypertensive people vising  Due to identifiable disorders: excessive renin secretion by the kidneys, arteriosclerosis and endocrine disorders such as hyperthyroidism and Cushing syndrome (due to abnormal adrenal gland functioning).  Treatment of secondary hypertension is directed towards correcting the causative problem. stroke lead to - blood Malignant hypertension: rise quickly  Develop quickly and reaches critical levels that can trigger lethal complications such as cerebral edema. This is defined as BP greater than 180/110mmHg with signs of papilloedema and/or retinal hemorrhage → medical emergency I blood vessels can burse secondary hyperfasive of people. ↳ 10 % ↳ excessive renin secretion from kidney hyperthyrodism , , Chung syndrome. Is correcting the causative problem. Malignant hypertensive cerebel edus. is critical level develop quickly that a can Liger with of papilodere/retind hoorrhage BP & 100/110 sign stroke strokattack Blood Vesselsdae blood vessels damage in heat kidny failure - In Major effects of Hypertension  MAP Terms to know before we start  Mean Arterial pressure is the average pressure tending to pushblood through the systemic circulation.  Normal value:100mmHg Mean arterial pressure= Cardiac output xTotal peripheral resistance  Cardiac output is defined as “quantity of blood pumped into theaorta each minute by the heart”. Normal value: 5 liter/min  Peripheral resistance: It is the amount of friction the blood encounters as it flows through the blood vessels.  Constriction/narrowing of the vessels (sympathetic/ atherosclerosis)  Increase blood vol/increase blood viscosity Peripher  Preload and After load  Preload: is used to describe  After load: is strictly “The volume of blood that defined as “the pressure fills the ventricle during that must be overcome for diastole” The relationship is the heart to pump blood as follows: into the arterial system during each systole. the volume of the ↑vol of blood in ↑venous return left ventricle blood that fills the ventricle during diastile. ↑strech/wall ↑pressure in tension in left ventricle left ventricle  Mechanisms of controlling blood pressure  In both normal and hypertensive individuals, cardiac out putand TPR are controlled mainly by two overlapping control mechanisms: 1. The Baroreflexes mediated by the sympathetic nervous system 2. The Renin - angiotensin aldosteron system  Baroreceptor and the sympathetic nervous system  Baroreceptors are non-capsulated nerve ending that are stimulatedwhen stretched.  wa wi pinje They are located in carotid sinus, aortic arch, walls of atrium, walls of left ventricle, pulmonary trunk. the main Rein is  Baroreceptor reflex: CaAoWaPuWa 1. An increase in arterial pressure stretches the baroreceptors in the carotidsinus and aortic arch. 2. Impulses from carotid sinus send to vasomotor centers through vagus nerves. 3. If these receptors are stimulated by increase of blood pressure then theycan cause vasodilatation & a decrease in heartrate 4. If stimulated due to fall in BP the opposite result will occur.  Baroreceptor and the sympathetic nervous system  Baro-reflex involving the sympathetic nervous system are responsible for the rapid moment to moment regulation of blood pressure.  A fall in BP causes stimulation of pressure sensitive baroreceptors to send a signal to cardiovascular centers in spinal cord.  This prompt a reflex response to increase sympathetic and decrease parasympathetic output to the heart and vessels, resulting in vasoconstriction, increase in TPR, increase in cardiac output and increase in BP.  ↑Activation Of β1 ↑ cardiac Adreno receptor on heart output ↑ BP ↑Sympathetic activity ↑Activation of α1 ↑ peripheral Adreno resistance receptor on smooth muscle Decrease in BP Response mediated by the sympathetic nervous system Baroreceptor Reflex  Renin- angiotensin- aldosteron system - -  Primary pathway in controlling BP. secreted when hypotension with sodium associate hypen in Kidney tiger low sodium renin -  Renin is an enzyme, secreted by the kidneys in response to low BP or when help decrease Na+ flowing through the kidneytubules. -ACE enzyme -  In a series of enzymatic reaction angiotensin I is converted into angiotensin II (in lungs-a potent vasoconstrictor) in the presences of an enzyme called angiotensin converting enzyme (ACE). ACE (also called kininase) is mainly located in the endothelial lining of blood vessels which is the site of production of most angiotensin II. This same enzyme also metabolizes bradykinin, an endogenous substance with strong vaso-dilatingproperties.  The intense vasoconstriction of arterioles caused by angiotensin II raises BP by increasing peripheral resistance. 70-90 % eat salty = thirsty water in blood  Angiotensin II also stimulates secretion of aldosteron which thus increase Na+ reabsorption in the kidney. hypertension = Blood volume ↑  ↑Renin ↑ AngiotensinII ↑ peripheral resistance ↑ BP ↑Aldosteron ↓Renal blood flow ↓Glomerular ↑ Na+,H2O ↑BloodVolume, filtration rate retention ↑Cardiac output Decrease in BP Response mediated by the renin-angiotensin-aldosteron system Management of Hypertension  Non Pharmacological management  Weight reduction: Most beneficial in patients who are >10%overweight, a weight loss as little as 4.5 kg can significantly decreases BP.  Cessation of smoking: able to reduce other cardiovascular risk, as smoking can acutely increase blood pressure.  Healthy eating: diet rich in fruits, vegetables, and dairy products with low saturated fat can be helpful in high BP management. Sodium restriction: Food rich in sodium content can cause increase in BP, elderly pts more sensitive.  Non Pharmacological management  Avoidance of alcohol intake: Alcohol has an acute effect in increasing BP  Regular physical exercise: simple exercise such as aerobic (walking) is better then resistance type (weight lifting)  Others: Stress management (stimulates steroid secretion), dietary supplementation, healthy life style, avoid sedentary life style, sports etc.  Pharmacological management  A:Drugs that alter sodium and waterbalance  Loop diuretics LPT laup diuretics  Thiazide diuretics ↳ sparing  Potassium sparing diuretics Thiazida:  B: Drugs that alter sympathetic nervous system functions  α2 - agonist  β – blockers  α- blockers - doagonis B-blocks.  C: Vasodilators d-blockers   Hydralazine Minoxidile Hy So Mica Vapodilativ  Sodium nitroprusside  Calcium channel blockers Adml a  D: Inhibitors of angiotensin  ACE inhibitors nitroparticle  ARBs calcium nual Minoxidile blocks Altus Na Ho balare diureties Loo um sparing diuretics Thinside diuretic Altus SNS do-artigomit d-blocks B-blockes Varidilators Hydmlaeh preside in Minoxidile Ca crunml blockers Inhibitor of angiotensin Inhibitor > ACE - Al's Sites of action of Antihypertensiveagents - Es Fillation thid from blood ↳ Me movement at - lamen of mphron. rabrorption evementat specfic compone from Che bal into block limest - tabular Erectio -diminition from the body in wire. Santian compone trarportion atlabla specific lan Pha blood into -  Drugs that Alter Sodium and WaterBalance vascular resistance  Loop diuretics (LD) of odterels Game > BP >  Thiazide diuretics (TD) ↓ hypertension  Potassium sparing diuretics (PSD) blood volume decrease sodium = blood volume  Diuretics lower BP by 1) depleting body sodium stores→ bloodvolume reduced→ cardiac output reduced; 2) reduce peripheral resistance. Remove Na in body to ↓ BV  Sodium contributes to vascular resistance.  May be used as first line agents. Enhance efficacy of otherantihypertensives.  TD are appropriate for most mild /moderate cases, with normal renal function. LD are for more severe cases, renal insufficiency and cardiac failure.  Serum potassium level should be monitored closely in patients proneto arrythmias and on digoxin+TD Diuretics can lower the BP by body store sheeving Na ↓ Blood volum - cariae output ↓ peripheral resistance thiazide Loop -mild/moderate ass > would neve ↳ Bee a sound insufficiency. > heart Failure  all this happened in E kidny Adverse effect loop make hypokalemia Thiazides 7 patient kt-sparing warndto remove in blood Na Na Loop 25% reduce blood better to ↳Furosemide 3. drug Na volume. Nat k"-sparing 15 % 5% absorb can Thiazide T Nat ↳ Spironolactors balance ↳ de level ↓Amiloterone i Na ↳ hydrochlowthiacea with & loop thiazide.  Loop diuretics decreased renal vascular resistance, increased renal blood flow, increase Ca+ in urine. Eg Furosemide, bumetanide, torsemide Potassium sparing diuretics prevent K+ secretion by antagonising aldosterone ( spironolactone). Inhibition by direct aldosterone receptor antagonism and inhibition sodium in CCT(amiloride). ADR: potassium depletion (except PSD), magnesium depletion, impair glucose tolerance, increase serum lipid, increase uric acid, erectile dysfunction. Use of low doses minimizes these effects without impairing antihypertensive action. PSD can produce hyperkalemia (if use with ACE & ARB), spirinolactone can cause gynaecomastia.  # ADR renal Blood Thou - My depletion ↳ ↳ k+ 2 ↳& Cn in urive ↳ N renal vascularresistances. ↳ suumlipid a uric acid can cause hyperkalemi ↳ impair glucosefolerance PSDs secretion ↳ erectile dysfunction ↳ prevent ↳byantagonistaldesa Na in CCT PIE'S  Recommended Dosing for Diuretics Recommended Diuretics Starting Dose* Maximum Daily Dose* Hydrochlorothiazide 12.5 mg od 50 mg od Chlorthalidone 50 mg od 100 mg od Amiloride/hydrochlorothiazide 5 mg/50 mg 1 tablet od 2 tablets od Indapamide SR 1.5 mg od 1.5 mg od Indapamide 2.5 mg od 2.5 mg od * Referenced from 132th Edition, MIMS, 2013 Drugs that alter the sympathetic nervous system functions ↓ BRz a symphatific  Methyldopa newwl  Clonidine α2-agonist ChMet syste  Propranolol β-blockers Met Con  Metoprolol Promet  Prazosin and other alpha blockers Pro Met Sympathlytic W block symphatic  Major effects mediated by α and ß adrenoreceptors norepinephrine : prcpulseStet ADRENORECEPTORS ↑ BP α1 α2 ß1 ß2 e HBe - 100 Vasoconstriction Tachycardia Vasodilator Inhibition Slightly ↓ ↑peripheral of norepinephrine ↑ Lipolysis PR resistance sympathetic ↑ Myocardial Bronchodilation ↑ muscles & decrease Propanololat. ↑ BP contractility liver glycogen- Inhibition olysis Mydriasis soilation pupit of insulin release ↑ release of ↑closure of prostatic hyperplasia Glucagon N Internal sphincter Relaxed uterine of the bladder hard to pe smooth muscle  Alpha adrenergic blocking agents  These drugs profoundly affect BP  Competitively block α1 adrenoceptor. Blockade of these receptors reduce the sympathetic tone of the blood vessels, decrease inTPR and thus cause reduce BP.  ChoiceforHPTwithbenignprostatichyperplasia.  Combined α and β blockers offer enhanced effect (eg labetalol, carvedilolalso improvemortalityin heartfailure) fiel Ram Payoh -  Havefavorableeffecton lipid metabolism.  ADR:posturalhypotension,first-dosesyncope,reflextachycardia  Prazosin  MOA: Selective competitive blockers of α1 receptors, don't alter aplha 2 receptor activity and therefore do not usually causereflex tachycardia.  Decrease peripheral resistance, lower BP by arterial andvenous smooth muscles relaxation.  Therapeutic uses: HPT with Benign prostatic hypertrophy.  Adverse effects: Dizziness, Nasal congestion, Orthostatic hypotension, Tachycardia, Sexual dysfunction Ore Niat Sumage Anjat Dir Tidur Effects of α-1 Antagonists  Centrally acting α2 agonist  Agent: α-Methyldopa, Clonidine, Moxonidine, Guanabenz, OrthustrlikePityp slowly Guanfacine.  Reduce sympathetic outflow from vasomotor centers in the brain→reduce peripheral sympathetic activity & peripheral resistance  M.O.A: Methyldopa converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS to reduce TPR and BP. Clonidine acts directy as partial α agonist.  Clinical uses: to Treat HPT in pts with renalinsufficiency  ADR: drowsiness, dry mouth, headache, dizziness, mood change (subside after few weeks of tx). Clonidine should not be stopped suddenly (rebound HPT)  Recommended Dosing for Centrally Acting Agents Drug Starting dose Maximum dose α- methyldopa* 125 mg bd 500 mg tds Clonidine 500 mcg tds 4 mg tds 200 mcg od 600 mcg in divided doses To be avoided if GFR 400 mcg in divided dose (GFR 30.60) Moxonidine - -headache outflow CNSS drowsing to diminist adrenergic I ↓ TOR &BP  β-blockers  These drugs blocks the beta adreno-receptors in the heart, peripheral vasculature, bronchi, pancreas, and liver.  Useful in HPT when concomitant disease is present  ADR: hypotension, bradycardia, fatigue, insomnia, sexual dysfunction, nightmares, cold extremities, reduce HDL, increased tryglyceride levels, masking of hypoglycaemia, increased incidence of diabetes mellitus. FISH  Use caution in pregnancy  Should not be withdrawn abruptly.  Contraindicated in patients with uncontrolled asthma/ other obstructive airway disease, heart block, severe peripheral vascular disease.  ↓Activation of ↓ Cardiac ß1 receptor output On heart β Adrenoreceptor Decrease in blockers ↓peripheral Blood resistance Pressure ↓Renin ↓Angiotensin II ↓Aldosterone ↓sodium, waterretention ↓Blood volume Action of beta adrenoreceptor blocking agents  ß-blockers Starting Dose* Recommended Maximum Daily Dose* Acebutolol 200 mg bd 400 mg bd Atenolol 50 mg od 100 mg od Betaxolol 10 mg od 40 mg od Bisoprolol 5 mg od 10 mg od Metoprolol 50 mg bd 200 mg bd Propranolol 40 mg bd 320 mg bd Nebivolol 5 mg od 10 mg od * Referenced from 132th Edition, MIMS, 2013  Propranolol Dok Ikea cen  Blocks both β1 and β2 receptors.  Actions:  Cardiovascular: Negative inotropic and chronotropic effects causing reduction in cardiac output and oxygen consumption.  Bronchoconstriction: Blocking ß2 receptors can precipitate respiratory crisis in COPD or asthma patients. ß blockers are thus contraindicated in asthmatic patients.  Increased Na+ retention: ↓ BP causes ↓renal perfusion, resulting ↑Na+ retention and plasma volume. Give combination with diuretics.  Disturbances in glucose metabolism: ↓glycogenolysis and ↓glucagon secretion may lead to severe hypoglycemia in an insulin dependent diabetic patient. Careful monitoring is required.  Propranolol  Therapeutic uses: MAHH  Hypertension,Angina pectoris, Myocardial infarction, Arrhythmias  Adverse effects:  Bronchoconstriction (Lethal side effect), Sexual impairment (reason un known), Hypotension, Disturbances in metabolism (glycogenolysis), Bradycardia Bakpo Dio suko liking  Drug interactions:  Verapamil should not be given with beta blocker by mouth to avoid the risk of hypotension and bradycardia.  Preparation:  Propranolol hydrochloride 10mg (Don't stop taking this medication without doctor's advice.  Recommended Dosing for α-blockers Recommended Maximum Daily α-blockers Starting Dose* Dose* Doxazosin 1 mg 16mg od Prazosin 0.5 mg nocte 20mg in divided doses Terazosin 1 mg 5mg od * Referenced from 132th Edition, MIMS, 2013 α,β-blockers Recommended Dosing for  ,β-blockers α Starting Dose* Maximum Dose* Labetolol ** 100 mg bd 2.4 gm 3-4 times a day Carvedilol *** 12.5 mg od 50 mg od referenced from 132th Edition, MIMS, 2013. In the elderly start with 50 mg bd The dosage of carvedilol for patients with heart failure and angina pectoris is different from the doses indicated above. T  Vasodilators  Hydralazine  Minoxidil  Sodium nitroprusside  Calcium channel blockers Hy So MiCa  Direct Vasodilators  Vasodilators act by producing direct relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure.  Hydralazine is only available in parenteral formulation for hypertensive emergencies (M’sia).  Minoxidil is used for refractory hypertension (difficult to treat hypertension)  Use in combination with diuretics & β-blockers. Hok Aloh Susan Puloktidur  Use is limited by their ADR.  ADR: headache, tachycardia, salt & water retention, palpitations, angina. Minoxidil can cause hirsutism.  Hydralazine Hok AloH SuSoh Pulok  MOA: Dilate blood vessels by acting directly on Tidur smooth muscle cells.  Clinical uses: HPT (in combination with beta blockers and diuretics)  Adverse effects:  Headache  Nausea  Sweating -  Arrhythmia  Precipitation of - angina  Tachycardia Tok NegaraSedap Hok Paling Argentina  Recommended Dosing for Direct Vasodilators Drug Starting Dose Maximum dose Minoxidil 5 mg od 50 mg od Hydralazine 10 mg qid 50 mg qid  Sodium Nitroprusside  Powerful parenterally administered vasodilator  Uses: Hypertensive emergencies & HF  M.O.A: Dilates both arterial and venous vessels, resulting in reduce TPR and venousreturn  ADRs: Hypotension,Arrhythmias Ht  Calcium Channel Blockers (CCB)  The intracellular concentration of calcium plays an important role in maintaining the tone of smooth muscles and in contraction of myocardium.  Calcium enters muscle cells through special voltage sensitive calcium channels.  This triggers release of calcium from the sarcoplasmic reticulum and further increase the calciumlevel.  Calcium channel antagonists block the inward movement of calcium in the heart and smooth muscles of the coronary artery and peripheral vasculature.  This causes vascular smooth muscles to relax, dilation, reduction in TPR, reduction inBP.  Recommended when first-line agents are ineffective/contraindicated.  Effective in treating HPT with angina/ diabetes.  Dihydropiridines and non-hydropyridines.  Most agents have short half-lives, not recommended for long-term use. Long term CCB are now available.  ADR: constipation, dizziness, headache, fatigue, hypotension  Recommended dosing for CCBs Recommended Maximum Daily Dihydropridines Starting Dose* Dose* amlodipine 5 mg od 10 mg od felodipine 5 mg od 10 mg od isradipine 2.5 mg bd 10 mg bd lacidipine 2 mg od 6 mg od lercanidipine 10 mg od 20 mg od nifedipine 10 mg tid 20 mg tid Non-dihydropridines diltiazem 30 mg tid 120 mg tid diltiazem SR 100 mg od 200 mg od verapamil 80 mg tid 160 mg tid verapamil SR 240 mg od 240 mg od * Referenced from 132th Edition, MIMS, 2013  Inhibitors of Angiotensin Angiotensin Converting Enzymes (ACE) Inhibitors  Decrease sympathetic nervous system, aldosterone that reduce water & sodium retention, increase vasodilation of smooth muscle and bradykinin→ reduced BP Angiotensin II Receptor Blockers (ARBs)  ADR  ACEIs: cough, angioedema, hyperkalemia, skin rash, hypotension, fever, increase fetal mortality (contraindicated in pregnancy), acute renal failure, angioedema  Serum creatinine and potassium should be monitored in elderly and renal impaired patients.  ARB: similar to ACEI but risk of cough and angioedema are reduced.  effective in preventing diabetic nephropathy→ useful in hypertensive diabetics.  The combination of ACEI and ARB is not recommended in hypertensive with normal renal function.  Recommended Dosing for ARBs ARBs Starting Dose* Recommended Maximum Daily Dose* Candesartan 8 mg od 16 mg od Irbesartan 150 mg od 300 mg od Losartan 50 mg od 100 mg od Telmisartan 20 mg od 80 mg od Valsartan 80 mg od 160 mg od Olmesartan 20 mg od 40 mg od Recommended Dosing for ACEIs ACEIs Starting Daily Dose* Recommended Maximum Daily Dose* Captopril 25 mg bd 50 mg tds Enalapril 2.5 mg od 20 mg bd Lisinopril 5 mg od 80 mg od Perindopril 2 mg od 8 mg od Ramipril 2.5 mg od 10 mg od Imidapril 2.5 mg od 10 mg od *Referenced from 132th Edition, MIMS, 2013  Patient information  Patients withACEI induced angioedema should be educated to avoid all ACEIs infuture.  Patients with history of angioedema withACEIs should avoid ARBs as well (not contraindicated)  Direct Renin Inhibitors Selective renin inhibitor (DRI) New class of agent→ aliskiren Combined with other drugs for enhance effect. Block RAAS at first and rate-limiting step of the cascade Cause reduction plasma renin activity, which is increased in hypertensive patients. Well tolerated ADR: diarrhea , cough, rash, increased uric acid, gout, renal stones  Recommended DRI Starting Dose* Maximum Daily Dose* Aliskiren 150 mg/day 300 mg/day * Referenced from 132th Edition, MIMS, 2013 Thanks and Questions