Pharmacotherapy of Hypertension PDF

Pharmacotherapy of Hypertension Prof. Ahmet AKICI, M.D.  What is Blood Pressure? BP = CO x TPR (CO = HR x SV) – Stroke volume – affected by contractility and venous return – TPR is regulated by Norepinephrine, Epinephrine, Angiotensin II BP Classification...

Pharmacotherapy of Hypertension Prof. Ahmet AKICI, M.D.  What is Blood Pressure? BP = CO x TPR (CO = HR x SV) – Stroke volume – affected by contractility and venous return – TPR is regulated by Norepinephrine, Epinephrine, Angiotensin II BP Classification SBP (mmHg) DBP (mmHg) Normal < 120 and < 80 Prehypertension 120-139 or 80-89 Stage I hypertension 140-159 or 90-99 Stage II hypertension > 160 or > 100 JNC-7 Classification JAMA. 2014;311(5):507-520.  Epidemiology and CVD Risk Hypertension is the most common primary diagnosis in many countries. It is one of the most important preventable causes of premature morbidity and mortality. It affects more than 150 million people across Europe, over 1 billion globally, with a prevalence of 30-45% in adults, increasing with age to more than 60% in people aged >60 years, and accounting for 10 million deaths globally per annum. In Turkey, 31.8% of population have HT.  Epidemiology and CVD Risk The relationship between BP and CVD is continuous, consistent and independent of other risk factors – MI – Heart failure – Stroke – Kidney disease  Etiology Primary hypertension – 95% of all cases Secondary hypertension – 5% of all cases – Chronic renal disease – most common White coat hypertension – Common? – Caused by  vascular resistance – Harmless??  Benefits of Lowering BP Sustaining a 12 mmHg reduction in SBP over 10 years will prevent one death for every 11 patients treated with Stage I HT w/additional CVD risk factors Why treat HT? – 35-40%  in stroke morbidity and mortality – 20-25%  CAD events – 21%  vascular mortality – 52%  in CHF – 35%  in Left ventricular hypertrophy (LVH)  Patient Evaluation Evaluation of patients with documented HT has three main objectives 1-Assess lifestyle and identify other CV risk factors or concomitant disorders 2-Reveal identifiable causes of hypertension 3-Assess the presence or absence of target organ damage and CVD  Patient Evaluation Assess lifestyle and identify other CV risk factors or concomitant disorders Hypertension Microalbuminuria or est Smoking GFR < 60 ml/min Obesity Age Physical inactivity – Males > 55 yrs – Females > 65 yrs Dyslipidemia Family history of CVD Diabetes – Males < 55 yrs – Females < 65 yrs  Patient Evaluation Reveal identifiable causes of hypertension Sleep Apnea Chronic steroid Drug-induced therapy and Cushing’s Chronic kidney dz syndrome Primary aldosteronism Pheochromocytoma Renal vascular dz Coarctation of the aorta Thyroid or parathyroid disorders  Patient Evaluation Assess the presence or absence of target organ damage and CVD Heart – LVH or CHF – Angina or prior MI – Prior coronary revascularization Brain – Stroke or transient ischemic attack (TIA) Chronic kidney disease Peripheral arterial disease Retinopathy  Treatment Outline Goals of therapy Lifestyle modification Classification and management of BP for adults Pharmacologic treatment Compelling indications for individual drug classes Follow-up and monitoring  Goals of Therapy Reduce CVD and renal morbidity and mortality Treat to BP < 140/90 mmHg If possible, achieve SBP goal especially less than above it. Minimize side effects  Pharmacologic Treatment Classification of Antihypertensive Drugs by Their Primary Site or Mechanism of Action The renin-angiotensin-aldosterone system (RAAS) inhibitors: 1-Angiotensin converting enzyme inhibitors (captopril, enalapril, lisinopril, quinapril, ramipril, benazepril, fosinopril, moexipril, perindopril, trandolapril etc.) 2-Angiotensin II- receptor antagonists (losartan, candesartan, irbesartan, valsartan, telmisartan, eprosartan) 3-Direct renin inhibitors (aliskiren) Diuretics 1-Thiazides and related agents (hydrochlorothiazide, chlorthalidone, indapamide etc.) 2- Loop diuretics (furosemide, ethacrynic acid, bumetanide, torsemide) 3-Potassium-sparing diuretics (triamterene, amiloride, spironolactone, eplerenone) Calcium channel blockers (amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, nisoldipine, felodipine, isradipine, lacidipine, lercanidipine, benidipine /verapamil / diltiazem) Sympatholytic drugs 1-β-adrenergic antagonists (atenolol, metoprolol, bisoprolol, nebivolol, betaxolol, esmolol, acebutolol, celiprolol/ propranolol, nadolol, pindolol, oxprenolol, penbutolol, carteolol) 2-α-adrenergic antagonists (prazosin, terazosin, doxazosin, phenoxybenzamine, phentolamine) 3-Mixed -adrenergic antagonists (labetalol, carvedilol) 4-Centrally acting agents (methyldopa, clonidine, guanabenz, guanfacine, moxonidine) 5-Adrenergic neuron blocking agents (guanadrel, reserpine, guanethidine ) Vasodilators 1-Arterial (hydralazine, minoxidil, diazoxide, fenoldopam) 2-Arterial and venous (nitroprusside) The renin-angiotensin-aldosterone system (RAAS) inhibitors 1-Angiotensin converting enzyme inhibitors (captopril, enalapril, lisinopril, cilazapril, quinapril, ramipril, benazepril, fosinopril, moexipril, perindopril, trandolapril, spirapril, delapril, temocapril, zofenopril, imidapril) 2-Angiotensin II- receptor antagonists (losartan, candesartan, irbesartan, valsartan, telmisartan, eprosartan) 3-Direct renin inhibitors (aliskiren) Angiotensin Converting Enzyme (ACE) Inhibitors  ACE Inhibitors Mechanism of action Inhibition of ACE peptidyl-dipeptase This directly interferes with the conversion of angiotensin I to angiotensin II Renin is released from the juxtaglomerular apparatus in response to blood pressure Renin is responsible for converting angiotensinogen to angiotensin I Angiotensin II is a powerful vasopressor that also stimulates the release of norepinephrine and aldosterone – Promote vasodilation and decrease aldosterone, resulting in decresased sodium and water retention. – Impede bradykinin breakdown and vasodilator prostaglandins Peripheral arterial vasodilation – No significant change in HR, CO or GFR  ACE Inhibitors Compelling indications – Heart failure or MI – Diabetics – Non-diabetic kidney disease Prototype agents – captopril, enalapril – Other agents – lisinopril, cilazapril, quinapril, ramipril, benazepril, fosinopril, moexipril, perindopril, trandolapril, spirapril, delapril, temocapril, zofenopril, imidapril – Except for fosinopril (hepatic elimination), ACE inhibitors are cleared predominantly by the kidneys. – Patients with HT related to high renin levels may respond better. – Like beta-blockers, ACE inhibitors are most effective in HT patients who are white and young.  ACE-inhibitors mechanism Circulation RAA system short-term effects Tissue RA system long-term effects Adrenal medulla Blood vasoconstriction vessels Blood Vascular Angiotensin I vessels hypertrophy Sympathetic system ACE-ls Ingestion Thirst Local of liquids Brain Brain hemodynamic Water alteration loss ADH Blood volume Angiotensin increase Local Aldosterone Adrenal II Kidneys Kidneys hemodynamic cortex alteration Water retention Arrhythmias Heart Heart LVH  ACE Inhibitors Side effects – Cough 15-20% → bradykinin build-up. May require drug discontinuation – Hyperkalemia – Hypotension – Na+ and volume depletion – Skin rash, altered taste, agranulocytosis – Angioedema (< 1%) Medical emergency – requiring antihistamine and steroid tx – Kidney dysfunction in bilateral renal artery stenosis Watch renal function when first started - contraindicated in pregnancy and - contraindicated in bilateral renal artery stenosis - Potassium level must be monitored, and potassium supplements or spironolactone are contraindicated  Captopril – the first ACE inhibitor to be marketed. Enalapril - the second ACE inhibitor to be marketed. Converted to metabolite enalaprilat (active). Lisinopril - lysine derivative of enalaprilat. Except for lisinopril and captopril, other ACE inhibitors are pro-drugs. They metabolize active form as –”at” forms -enalapril →enalaprilat; - quinapril →quinaprilat; -ramipril →ramiprilat; - benazepril →benazeprilat; - fosinopril →fosinprilat; - moexipril →moexiprilat; - imidapril → imidaprilat; - trandolapril →trandolaprilat; - perindopril →perindoprilat.  Drug Interactions-ACE Inhibitors Lithium – lithium toxicity (weakness, tremor, excessive thirst, confusion) and/or nephrotoxicity NSAIDs – decreased effectiveness K+ or K+ sparing diuretics – lowering aldosterone levels, which in turn, can result in potassium retention Diuretics – vasodilation and relative intra-vascular volume depletion ACEIs and ARBs should not be used in combination. Angiotensin II- Receptor Antagonists/Blockers (ARBs)  ARBs Inhibit the activity of angiotensin II receptors on the blood vessel wall – promotes vasodilation Increase salt and water excretion Do not alter metabolism of bradykinin, norepinephrine, or substance P The ARBs available for clinical use bind to the AT1 receptor with high affinity and are generally >10.000- fold selective for AT1 versus the AT2 receptor. Compelling indications – similar to ACEI – Heart failure or MI – Diabetics – Non-diabetic kidney disease AT II-antagonist mechanism Angiotensinogen Renin Angiotensin I ACEI Non-ACE ACE Chymase, Cathepsin G Angiotensin II Tonin, CAGE, etc AT1 receptor AT2 receptor AT II receptor Increase the sympathetic activity antagonist Increase the aldosterone Vasoconstriction  ARBs Prototype agents – losartan, valsartan Others- candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan. Typically utilized in those intolerant to ACEI – Cough is much less frequent Firmly established benefit in diabetic patients similar but not superior to ACEI Angioedema – reports of cross-reactivity  ARBs Side effects – Similar to ACEI – but less cough, less incidence of angioedema Drug interactions – Similar to ACEI – Contraindications – similar to ACEI. !!! ACEIs and ARBs should not be used in combination.  Direct Renin Inhibitors Aliskiren: Selective renin inh. Side effects: Diarrhea, hyperkalemia less cough, less incidence of angioedema than ACEIs Contraindicated during pregnancy and hypersensitivity. Expensive ------------------------------------------------------------- Angiotensinogen RENİN Angiotensin I Diuretics 1- Thiazides and related agents 2- Loop diuretics 3- Potassium-sparing diuretics  Diuretics Primary mechanisms of action – Deplete Na+ (natriuesis) and reduce plasma volume – Persistent  total peripheral resistance – May produce up to 10-15 mmHg  in BP as monotherapy, efficacy even greater in combination with other agents – Types – thiazides, loop, and potassium-sparing Sites of Diuretic Action  Thiazide Diuretics Block Na+ reabsorption in the early distal tubule – mobilize Na+ and H20 from arterial walls, ultimately leading to  in PVR Thiazide effective drops dramatically with  GFR Thiazide diuretics in clinical trials – Reduce stroke – Reduce CHF – Reduce CAD Prototype drug – hydrochlorothiazide  Mechanism of Action Thiazides freely filtered and secreted in proximal tubule Bind to the electroneutral NaCl cotransporter Thiazides impair Na+ and Cl- reabsorption in the early distal tubule: “low ceiling”  Thiazide and Thiazide-like Diuretics Hydrochlorothiazide Chlorothiazide Methyclorothiazide Bendroflumethiazide Hydroflumethiazide Triclormethiazide Polythiazide Quinethazone Metolazone Chlorthalidone Indapamide  Pharmacokinetics of Thiazides Rapid GI absorption Distribution in extracellular space Elimination unchanged in kidney Variable elimination kinetics and therefore variable half-lives of elimination ranging from hours to days. T1/2 for chlorothiazide is 1.5 hours, chlorthalidone 44 hours.  Side Effects of Thiazide Diuretics Initially, they were used at high doses which caused a high incidence of adverse effects. Lower doses now used cause fewer adverse effects. Among them are: HYPOKALEMIA DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia HYPERURICEMIA because thiazides compete with urate for tubular secretion HYPERLIPIDEMIA; mechanism unknown but cholesterol increases usually trivial (1% increase) IMPOTENCE HYPONATREMIA due to thirst, sodium loss, inappropriate ADH secretion (can cause confusion in the elderly), usually after prolonged use Less common problems HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (all very rare) METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen HYPERCALCEMIA MAGNESIUM DEPLETION Weakness, lethargy, muscle cramps  Loop Diuretics Block Na+ reabsorption in the loop of Henle Inhibition of the apical Na-K-2Cl cotransporter of the TALH Provide more pronounced diuresis than thiazides – yet have a shorter duration of action and less effective at lowering BP Effective with  GFR – better option for patients with CHF  Loop Diuretics Prototype agent – furosemide – Torsemide, bumetanide, ethacrynic acid – Furosemide dosing IV to PO – 1:2 conversion – Potency: torsemide = bumetanide > furosemide Due to  bioavailability of furosemide = 60 to 65% Allergy caution – sulfonamide If loop diuretic needed utilize ethacrynic acid  Loop Diuretics Pharmacokinetics Rapid GI absorption, bioavailability ranges from 65-100% Also given i.m. and i.v. Rapid onset of action Extensively bound to plasma proteins Short half-lives in general Elimination: unchanged in kidney or by conjugation in the liver and secretion in bile.  Loop Diuretics Side effects – Similar to thiazide diuretics hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia dehydration and postural hypotension hypocalcemia (in contrast to thiazides) magnesium depletion hypersensitivity ototoxicity (especially if given by rapid IV bolus) Potassium Sparing Diuretics Inhibit the renal absorption of Na+ in the collecting tubule in exchange for K+ and H+ Weak antihypertensive agents when used as monotherapy Most commonly used in combination with thiazides – Effective against thiazide-related hypokalemia Potassium Sparing Diuretics Prototype agent – triamterene – Spironolactone, eplerenone , amiloride Spironolactone, eplerenone – aldosterone antagonist – Active metabolite of spironolactone: canrenone (active) Side effects – Hyperkalemia – Caution with ACE inhibitors – Gastrointestinal – diarrhea – Photosensitivity – Gynecomastia (Ald. antagonists) – Nephrolithiasis (triamterene) – Reversible azotemia (triamterine)  Drug Interactions - Diuretics Digoxin – diuretic-induced hypokalemia creates proarrhythmic state Lithium – increased lithium concentrations and lithium toxicity (weakness, tremor, excessive thirst, confusion) NSAIDs – decreased diuretic and antihypertensive efficacy as a result of decreased renal prostaglandin production Hypoglycemic agents – decreased insulin sensitivity, increased potassium loss  Therapeutic notes about Diuretics Thiazide diuretics are available as fixed-dose combinations with potassium-sparing or other antihypertensive drugs. Often used in combination with antihypertensive agents that impair vascular responsiveness (i.e., vasodilators) since blood pressure can become very sensitive to blood volume in the presence of these agents. Potassium supplements can be prescribed to compensate for hypokalemia in thiazide tx. The thiazides are not useful in patients with renal insufficiency (glomerular filtration rate < 40 ml/min).  Calcium Channel Blockers 1-Dihydropyridines 2-Non- dihydropyridines  Calcium Channel Blockers (CCBs) CCBs promote vasodilation by preventing the intracellular influx of calcium into vascular smooth muscle. Decrease total peripheral resistance and reduce BP. Verapamil, diltiazem, and the dihydropyridine family are all equally effective in lowering BP. Dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem. Compelling Indications – Angina – Diabetes – Bronchospasm – Renal disease  Calcium Channel Blockers Two types – Dihydropyridines – amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, nisoldipine, felodipine, isradipine, lacidipine, lercanidipine, benidipine. Potent vasodilators of peripheral and coronary arteries – Non-dihydropyridines – verapamil, diltiazem Less potent vasodilators, negative chronotropic and inotropic actions Do not alter serum lipids, glucose, uric acid or electrolytes. May not provide as much protection from CV events as B- blockers and ACEI, exception – stroke. Avoid immediate release dihydropyridine agents due to risk of MI, severe hypotension, cerebral ischemia and death (e.g. SL nifedipine).  Calcium Channel Blockers Side effects – The most important adverse effects are direct extension of their therapeutic action; – Non-dihydropyridines: Depression of contractility, HF, AV nodal blockade, bradycardia, hypotension. Verapamil > diltiazem – Dihydropyridines can cause tachycardia – The most common adverse effects: flushing, headache, dizziness, fatigue, hypotension. – Lower extremity edema – Constipation, nausea All, but esp. verapamil – Gingival hyperplasia. esp. verapamil  Amlodipine - a dihydropyridine; relatively selective vasodilator and less cardiac depression than verapamil or diltiazem. It is used in tx of HT and CAD. Side Effects: peripheral edema, fatigue, tachycardia, headache, flushing, gingival hyperplasia. Diltiazem - intermediate action on heart and blood vessels. It is used in tx of HT, CAD and arrhythmia. Side Effects: dizziness, headache, edema, bradycardia Verapamil -phenylalkylamine class - greatest effect on heart. It is used in tx of HT, CAD, arrhythmia, and cluster headaches. Side Effects: dizziness, headache, edema, constipation, bradycardia , gingival hyperplasia.  Drug Interactions-CCBs CCBs are substrates of cytochrome p450 enzymes, especially CYP3A4, so drugs that induce or inhibit the CYP3A4 enzyme or foods such as grapefruit juice may affect the metabolism of CCBs. H2 Antagonists –  concentrations of nifedipine, nitrendipine Rifampin and barbiturates – Marked  in serum conc. of verapamil, diltiazem and nifedipine Macrolides and Azole antifungals – Great inhibitors -  concentrations of verapamil, diltiazem, nifedipine, felodipine Cardiovascular agents -  serum conc. of many – Digoxin, statins, antiarrhythmics, beta blockers Immunosuppressants – Cyclosporine, tacrolimus and sirolimus  Sympatholytic Drugs 1- β-Adrenergic antagonists 2- α-Adrenergic antagonists 3- Mixed-Adrenergic antagonists 4- Centrally acting agents 5- Adrenergic neuron blocking agents  Beta Adrenergic Antagonists Mechanism of action: – Decrease contractility and output – Lower heart rate – Diminish sympathetic reflex – Decrease renin release – Reduce peripheral norepinephrine release Compelling indications – CVD – Angina, MI, CHF – Atrial fibrillation  Beta blockers Use: – Blood pressure control – Control of angina – Prolongs survival after MI (prevents arrhythmias) – Prolongs survival in heart failure – Treatment of certain abnormal heart rhythms – Prevention of migraines – Treatment of glaucoma – Treatment of hyperthyroidism  Beta blockers Prototype agents – Atenolol, metoprolol, propranolol Cardioselectivity – utilize Beta-1 selective in patients with history of asthma or COPD, PVD or Raynaud’s dz ISA – May increase HR in those with low resting HR – Can worsen angina and CHF Lipid solubility – Highly lipophilic – dependent on hepatic and renal fx – Penetrate CNS – this may be good or bad depending on the patient – Bioavailability is limited to varying degrees for most beta blockers with the exception of betaxolol, penbutolol, pindolol.  Beta Blocking Agents Non-Selective Selective With Alpha-Blocking Activity - ISA + ISA - ISA + ISA Nadolol Pindolol Atenolol Acebutolol Labetalol Propranolol Oxprenolol Metoprolol Celiprolol Carvedilol Penbutolol Bisoprolol Carteolol Nebivolol Esmolol Betaxolol  Beta blockers Side effects – Bradycardia and hypotension – Beta-blockers must be withdrawn gradually to avoid withdrawal – Aggravation of acute CHF – Fatigue, lethargy, confusion, nightmares, depression, – Bronchospasm – Vasospasm, vasoconstriction Unopposed alpha, Raynaud’s phenomenon and PVD – Masking of hypoglycemic symptoms Especially in those with tight glycemic control – Impaired exercise tolerance – Insomnia – Erectile dysfunction.  Beta blockers Contraindications – Bradycardia, conduction abnormalities, COPD, diabetes, severe unstable left ventricular failure, Greater than 1st degree heart block. Patient information – Side effects Important to counsel male patients! – Abrupt withdrawal Discontinuation should be over 5-10 days to avoid rebound angina or hypertension Associated with sudden cardiac death and AMI o Propranolol - "nonselective"; useful in mild to moderate hypertension; in severe hypertension, used as adjunct to prevent reflex tachycardia that accompanies treatment with direct vasodilators. o Nadolol - "nonselective"; long half-life (t1/2: 24 hours), better patient compliance. o Pindolol - "nonselective"; partial agonist (intrinsic sympathomimetic activity (ISA)); less bradycardia than other beta- blockers. o Metoprolol, Atenolol, Bisoprolol, Nebivolol, Betaxolol : beta1 "selective“ and ISA(-). o Acebutolol and Celiprolol: beta1 "selective“ and ISA(+). o Esmolol - beta1 selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases (t1/2: 9 minutes). It is used iv.  Drug Interactions-Beta blockers Hypoglycemic agents – Mask symptoms of hypoglycemia Verapamil and diltiazem – Increase concentration of metoprolol, propranolol and others Cimetidine – Increase concentration of metoprolol, propranololand others Digoxin, amiodarone – pharmacodynamic – Bradycardia, delayed AV conduction, arrhythmias  Alpha-Adrenergic Antagonists Selective alpha-1-blockade produces arteriole and venous vasodilation and reduces preload and afterload during rest and exercise Agents – prazosin, terazosin, doxazosin, urapidil, phenoxybenzamine, phentolamine Compelling indication – BPH Side effects – First dose syncope – dose at bedtime – Tachycardia – Na+ and water retention – CNS – fatigue and depression  Prazosin o less tachycardia than direct vasodilators o Side Effects: first dose produces precipitous fall in blood pressure, dizziness, headaches, weakness, decrease LDL/HDL o Therapeutic Notes: Drugs do not impair exercise tolerance. Drugs decrease blood pressure only to a certain extent, since fall is directly related to that component of vascular resistance maintained by sympathetic activation. Prazosin and other alpha blockers are more effective when used in combination with other agents, such as a beta- blocker and a diuretic, then when used alone.  Urapidil Alpha-1 adrenergic antagonist and seratonin agonist (5HT-1A) It is given orally for tx of HT and iv in hypertensive emergencies.  Phenoxybenzamine and Phentolamine The nonselective agents, phenoxybenzamine and phentolamine, are useful in diagnosis and treatment of pheochromocytoma.  Mixed -Adrenergic antagonists (labetalol, carvedilol) Labetalol - has a 1: 3 ratio of alpha: beta adrenergic receptor antagonism after oral dosing. -useful in hypertension of pheochromocytomas and hypertension emergencies. Nonselective beta blocker Mild alpha blocker Duration 2 to 18 hours Hepatic metabolism and renal excretion side effects: orthostatic hypotension; sexual dysfunction, ….  Mixed -Adrenergic antagonists (labetalol, carvedilol) Carvedilol - The ratio of alpha- to beta –adrenergic receptor antagonist potency for carvedilol is 1:10. As with labetalol, the long-term efficacy and side effects of carvedilol in hypertension are predictable based on its properties as a beta and alpha-1 adrenergic receptor antagonist. In addition, mild reversible hepatocellular injury has been reported with carvedilol.  Central alpha-2 agonist Reduces sympathetic outflow from the brain secondary to direct stimulating effects on alpha-receptors in the vasomotor center of the medulla. Decreases in BP are associated with reductions in peripheral vascular resistance and decreases in heart rate (secondary to increased vagal tone). Risk of rebound HT, tachycardia with abrupt cessation of tx Agents – clonidine, guanabenz, guanfacine, methyldopa, moxonidine  CNS Sympathomimetic 2 Adrenergic Receptor Stimulation Efferent Sympathetic Activity Decrease in Arterial Blood Pressure  Central alpha-2 agonist Primarily used as 3rd or 4th line treatment Side effects – Orthostatic hypotension, dizziness blunted baroreceptor response – Drowsiness, sedation, and dry mouth – Hepatotoxicity, hemolysis – methyldopa Drug interactions – TCAs decreased antihypertensive effectiveness due to antagonism at central alpha-2 receptors – MAOI Contraindicated with many centrally acting agents due to risk of hypertensive crisis  Central alpha-2 agonist Clonidine - alpha2 agonist at medullary cardiovascular regulatory centers; decreases sympathetic outflow from CNS. Side Effects: sedation and dry mouth, marked bradycardia is rare, but can be significant; side effects may be reduced by transdermal preparation (although discontinued in 20% patients because of contact dermatitis). Selected Drug Interactions: may potentiate actions of other CNS depressants. Therapeutic Notes: – must withdrawal slowly to prevent rebound hypertension, nervousness, insomnia, etc.; must warn patients about missing doses. – available in tablet form, or as a transdermal system; patients must be instructed to dispose of transdermal systems properly – has little effect on plasma lipids.  Dopa -Methyldopa Dopa decarboxylase Dopamine -Methyldopamine DA −Hydroxylase -MethylNepi 2 Stimulation Clonidine (—) Sympathetic Outflow  Central alpha-2 agonist – Methyldopa - converted to methyldopamine and then methylnorepinephrine; methylnorepinephrine acts on central alpha-2 receptors to decrease blood pressure chiefly by decreasing sympathetic outflow from CNS Side Effects: sedation, nightmares, movement disorders, hyperprolactinemia; rarely hypersensitivity, anemia, orthostatic hypotension, hepatotoxicity, hemolysis Selected Drug Interactions: – MAOIs – levodopa Therapeutic Notes: – It can be used in pregnant women. – Effective when used with a diuretic – Not used as initial treatment  Adrenergic neuron blocking agents (guanadrel, guanethidine, reserpine ) Guanadrel - specifically inhibits the function of peripheral postganglionic adrenergic neurons Mechanism: Targets peripheral adrenergic neurons where it inhibits sympathetic function. Actively transported into the neuron by the NE reuptake pump; then concentrated in the secretory vesicles. It replaces NE in the vesicle and is secreted instead in response to normal nerve stimulation (probably the 1˚ mechanism of its neuron blocking action). Possesses no activity at post-synaptic receptors.  Guanadrel G G G G  Guanadrel All pharmacologic effects -- result from the sympathetic block. Decreases TPR Expands plasma volume -- can lead to pseudotolerance: needs a diuretic Other drugs that are also transported by the NE reuptake pump will inhibit the effectiveness of guanadrel: tricyclic antidepressants (TCAs), cocaine, chlorpromazine, ephedrine, phenylpropanolamine, amphetamine. Supersensitivity develops Not as monotherapy or initial therapy because of the orthostatic hypotension.  Guanadrel Side Effects: - Postural hypotension - Sexual dysfunction - Diarrhea - Drug interactions: TCAs, cocaine, chlorpromazine, ephedrine, phenylpropanolamine, and amphetamine.  Guanethidine - prevents norepinephrine release from nerve terminals; effective, severe side effects; reserved for severe hypertension -Side Effects: marked orthostatic hypotension, diarrhea, bradycardia, impotence; does not enter CNS -Selected Drug Interactions: TCAs  Reserpine - Rawolfia Serpentina Binds to storage vesicles in CNS and peripheral adrenergic neurons where it blocks the ATP-dependent proton pump (translocase) that transports amines into the vesicle. The binding is irreversible. New vesicles have to be synthesized. The antihypertensive effect probably results from both the central and peripheral actions. Binding results in a dysfunctional vesicle: nerve endings lose the ability to concentrate and store NE and DA. The catecholamines leak into the cytoplasm where they are metabolized by MAO. Little or no neurotransmitter is released when the nerves are depolarized.  Reserpine – disrupts norepinephrine vesicular storage; probably both central and peripheral action; can be used to treat mild to moderate hypertension Side Effects: severe psychological depression, sedation, extrapyramidal effects resembling Parkinson’s disease, diarrhea, peptic ulcer, bradycardia, postural hypotension, nasal congestion Selected Drug Interactions: – may potentiate effects of CNS depressants – MAOIs  Vasodilators 1- Arterial vasodilators 2- Arterial and venous vasodilator  Arterial Vasodilators Direct relaxing effect on the musculature of the precapillary arterioles, thereby lowering total peripheral resistance Little or no effects on venous capacitance vessels and does not effect the functioning of the carotid or aortic baroreceptors Agents – hydralazine, minoxidil, diazoxide, and fenoldopam. Hydralazine – interferes with Ca transport in smooth muscle; orally effective (but bioavailability is low), used both for treating resistant hypertension and emergencies o Side Effects: tachycardia, palpitation, aggravation of angina, fluid retention, anorexia, nausea, vomiting, sweating, flushing, headache, rash, lupus-like syndrome. Minoxidil Orally effective, used mainly for treating resistant hypertension. It opens potassium channels in smooth muscle membranes. It must be used in combination with a beta-blocker and a loop diuretic. o Side Effects: tachycardia, palpitation, aggravation of angina, fluid retention, nausea, vomiting, sweating, flushing, headache, hypertrichosis (topical minoxidil is now used as a stimulant to hair growth for correction of baldness). Diazoxide - used to treat hypertensive emergencies; long duration of action. It prevents vascular smooth muscle contraction by opening potassium channels and stabilizing the membrane potential at the resting level. Side Effects: severe tachycardia, prolonged hypotension, nausea and vomitting. Diazoxide inhibits insulin release from the pancreas and is used to treat hypoglycemia secondary to insulinoma. Fenoldopam – is a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It is a peripheral DA-1 receptor agonist. Side Effects: tachycardia, flushing, headache, increasing intraocular pressure.  Arterial and Venous Vasodilator Sodium Nitroprusside (SNP) - used to treat hypertensive emergencies (only by iv.); immediate onset, but brief duration of action; SNP dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. It is metabolized by blood vessels to its active metabolite, nitric oxide. SNP inactivated by light- wrap in aluminium foil ! Side Effects: hypotension, nausea, vomiting, muscle twitching, cyanide poisoning.  Compelling Indications Compelling Indication Initial Therapy Options Heart failure Thiazide, BB, ACEI, ARB, ALDO-Ant MI BB, ACEI, ALDO-Ant High CAD risk Thiazide, BB, ACEI, CCB Diabetes ACEI, ARB, CCB Chronic Kidney Dz ACEI, ARB Recurrent Stroke Thaizide, ACEI Prevention  Compelling Populations High-Risk Hypertensives – Blacks – Diabetics – Elderly – Renovascular disease – Pregnancy  Diabetics Direct correlation between systolic BP and decline in GFR As little as a 2 mmHg  BP results in significant reductions in CVD. Preferred agents – ACEI or ARBs !!! ACEIs and ARBs should not be used in combination.  Elderly Population with the lowest BP control, yet the most to gain! Issues – polypharmacy, altered drug metabolism, physiological changes In general, patients will require combination therapy to achieve goal BP Susceptible to volume depletion – orthostatic hypotension Cognitive impairment Fixed incomes  Renal vascular Disease ACEI or ARBs Caution – Rapid and profound drop in BP as well as renal failure Avoid in bilateral RAS  Pregnancy Almost all cardiovascular drugs are either risk category C or D. Chronic/transient hypertension vs. preeclampsia Problem – not much data from controlled clinical studies Tx: Methyldopa, Labetalol, CCBs, Hydralazine, BBs? In severe hypertension in pregnancy, drug treatment with i.v. labetalol, oral methyldopa, or oral nifedipine is recommended. Intravenous hydralazine is a second-line option. Avoid: – ACEI, ARB – Diuretics?  Combination Therapy Theoretical requirements – The combination must have superior efficacy to monotherapy – Each component must contribute to the therapeutic effect – Dosage forms must be satisfactory regarding bioavailability, absence of unwanted interactions, and careful selection of doses for each component !!! ACEIs and ARBs should not be used in combination.  Causes of Resistant HT Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication – Inadequate doses – Compliance – Drug interactions – OTC/herbals/dietary supplements Excess alcohol intake Identifiable causes of HT  Promote Patient Compliance Educate patient regarding proper use of medicine as well as disease state Include social support networks Include the patient in decision making Avoid drugs with numerous side effects Simplify the drug regimen – Minimize the # of pills, frequency, and inconvenience Provide positive reinforcement Maintain continuity of care Individualize treatment  Additional Considerations in Antihypertensive Drug Choices (I) Potential favorable effects ▪ Thiazide-type diuretics useful in slowing demineralization in osteoporosis. ▪ BBs useful in the treatment of atrial tachyarrhythmias/fibrillation, migraine, thyrotoxicosis (short-term), essential tremor, or perioperative HT. ▪ CCBs useful in Raynaud’s syndrome and certain arrhythmias. ▪ Alpha-blockers useful in prostatism.  Additional Considerations in Antihypertensive Drug Choices (II) Potential unfavorable effects ▪ Thiazide diuretics should be used cautiously in gout or a history of significant hyponatremia. ▪ BBs should be generally avoided in patients with asthma, reactive airways disease, or second- or third-degree heart block. ▪ ACEIs and ARBs are contraindicated in pregnant women or those likely to become pregnant. ▪ ACEIs should not be used in individuals with a history of angioedema. ▪ Aldosterone antagonists and potassium-sparing diuretics can cause hyperkalemia.  Pharmacologic Treatment The renin-angiotensin-aldosterone system (RAAS) inhibitors: 1-Angiotensin converting enzyme inhibitors (captopril, enalapril, lisinopril, quinapril, ramipril, benazepril, fosinopril, moexipril, perindopril, trandolapril, etc.) 2-Angiotensin II- receptor antagonists (losartan, candesartan, irbesartan, valsartan, telmisartan, eprosartan) 3-Direct renin inhibitors (aliskiren) Diuretics 1-Thiazides and related agents (hydrochlorothiazide, chlorthalidone, indapamide etc.) 2- Loop diuretics (furosemide, ethacrynic acid, bumetanide, torsemide) 3-Potassium-sparing diuretics (triamterene, amiloride, spironolactone, eplerenone) Calcium channel blockers (amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, nisoldipine, felodipine, isradipine, lacidipine, lercanidipine, benidipine /verapamil / diltiazem) Sympatholytic drugs 1-β-adrenergic antagonists (atenolol, metoprolol, bisoprolol, nebivolol, betaxolol, esmolol, acebutolol, celiprolol/ propranolol, nadolol, pindolol, oxprenolol, penbutolol, carteolol) 2-α-adrenergic antagonists (prazosin, terazosin, doxazosin, phenoxybenzamine, phentolamine) 3-Mixed -adrenergic antagonists (labetalol, carvedilol) 4-Centrally acting agents (methyldopa, clonidine, guanabenz, guanfacine, moxonidine) 5-Adrenergic neuron blocking agents (guanadrel, reserpine, guanethidine ) Vasodilators 1-Arterial (hydralazine, minoxidil, diazoxide, fenoldopam) 2-Arterial and venous (nitroprusside)