Antihypertensives Part One PA 2024 (1) PDF

ANTI-HYPERTENSIVES PART ONE FIRST LINE DRUGS  Objectives For each of the drugs to the extent covered in class, distinguish between: Available agents Mechanism of action Clinical indications Adverse/toxic effects, contraindications, interactions and precau...

ANTI-HYPERTENSIVES PART ONE FIRST LINE DRUGS  Objectives For each of the drugs to the extent covered in class, distinguish between: Available agents Mechanism of action Clinical indications Adverse/toxic effects, contraindications, interactions and precautions Given a clinical scenario, choose the most appropriate therapeutic agent from those listed in the presentation  Required Reading 1.) Pharmacology, Sixth Edition by Brenner, GM. Chapter 10  JNC8 Guidelines https://sites.jamanetwork.com/jnc8/ JNC8 Guidelines  The Line-Up First-Line Drugs Thiazide diuretics ACE inhibitors (ACEIs) Angiotensin receptor blockers (ARBs) Direct renin inhibitors (not “spun-off” as a separate category in JNC8, Recommendation 6) Calcium channel blockers (CCBs) ……….and the multitude of fixed dose combinations Physiology of Blood Pressure Regulation Key Fundamental Relationships CO X TPR = MAP R=8VL/p r4 HR X SV = CO Physiology of Blood Pressure Regulation  Diuretics Diuretic agents have an important role in the management of hypertension and have been around since the 1950s. They are sometimes used as a single drug (monotherapy) in cases of mild hypertension, as they can lower blood pressure by 10-15 mm Hg in most patients. More often, however, they are used in conjunction with other antihypertensive agents (combination therapy), as  3 Major Classes of Diuretics 1. THIAZIDES (or thiazide-like*) Examples: Chlorothiazide (Diuril) Hydrochlorothiazide (Hydrodiuril, Microzide) Chlorthalidone (Thalitone, generics) Metolazone (Zaroxolyn) * Indapamide (Lozol) *  3 Major Classes of Diuretics 2. LOOP DIURETICS ("High Ceiling" Diuretics) Examples: Furosemide (Lasix) Bumetanide (Bumex) Torsemide (Demadex)  3 Major Classes of Diuretics 3. K+-SPARING DIURETICS / ALDOSTERONE RECEPTOR BLOCKERS Examples: Amiloride (Midamor)– K+-sparing Triamterene (Dyrenium) -- K+- sparing Spironolactone (Aldactone) - Aldosterone receptor blocker Eplerenone (Inspra) – Aldosterone receptor blocker  Thiazides All oral diuretic drugs are effective in the treatment of hypertension, but the thiazides have found the most widespread use. Why? They are the most extensively studied and most consistently effective in clinical trials There is much “experience” from using them in millions of patients – they are generally well tolerated and enhance the efficacy of other anti-hypertensive agents The duration of action is typically between 18-24 hours which makes once-daily dosing feasible --- a huge convenience to the patient, which ultimately favors compliance Thiazid es SHORT-TERM Mediated by a decrease in CO Thiazides block the Na+Cl- symporters in the DCT of nephrons responsible for Na+Cl- reabsorption Hence, Na+Cl- is excreted along with H20, thereby lowering blood volume Thiazid May see a reflex ↑ in SNS activity es LONG-TERM (to ↑ TPR) and ↑ in RAA system Mediated by activity -- Why? a decrease in Could you TPR = SVR = counteract this? PVR How?  by If the having an compensatory arterial changes are vasodilatory great enough, effect the anti- How?  not hypertensive well effect of the understood thiazide may be lost The long- term effect by take In general, most diuretics (not all) increase H2O elimination as a consequence of increasing renal electrolyte excretion  Thiazides When a thiazide diuretic is utilized as monotherapy, it should be administered in a low dose; clinical evidence has demonstrated that anti-hypertensive effects can be achieved in many patients with as little as 12.5 mg of chlorthalidone or hydrochlorothiazide (Hydrodiuril) daily Thiazides have a relatively low therapeutic ceiling effect  Thiazides Most patients will respond to thiazide diuretics with a reduction in blood pressure within 2-4 weeks, although a minority will not achieve maximum reduction in arterial pressure for up to 12 weeks on a given dose. Therefore, doses should not be increased more often than every 2-4 weeks. Thiazide diuretics are particularly useful in the treatment of African-American or elderly patients (>60 years). These patients tend to respond best to thiazide diuretics compared to other anti- hypertensives – why is unclear. Thiazide diuretics are not effective in patients with inadequate kidney function; loop diuretics  Thiazides – Adverse Effects Erectile Dysfunction A common side effect; MOA not entirely clear, but may be linked to hypovolemia Hypovolemia Be cautious in the elderly; good reason to start with low dose Hypokalemia Occurs in ~ 70% of patients (mainly with higher doses) Need to be careful with those patients predisposed to  Thiazides – Adverse Effects Hyperuricemia MOA not entirely clear Need to be careful with those patients with gout Hypercalcemia MOA not entirely clear Increased calcium can raise the excitability of the heart  Thiazides – Adverse Effects Dyslipidemia MOA not entirely clear Mild elevations in LDL & triglycerides, slight reductions in HDL Should be used with caution in patients who are already dyslipidemic Hyperglycemia MOA not entirely clear Occurs in approx. 10% of patients Key Point  The thiazide-induced metabolic and electrolyte abnormalities can generally be minimized or avoided and the antihypertensive efficacy maintained by the use of low doses (e.g., 12.5-25 mg vs. 50 mg HCTZ)  Thiazide Combinations Thiazide + ACEI Lotensin HCT (benzaepril + HCTZ) Vaseretic, Zestoretic (enalapril + HCTZ) Prinzide (lisinopril + HCTZ) Uniretic (moxepril + HCTZ) Thiazide + ARB Atacand HCT (candesartan + HCTZ) Avalide (irbesartan + HCTZ) Benicar (olmesartan + HCTZ) Diovan HCT (valsartan + HCTZ) Edarbyclor (azilsartan + chlorthalidone) Hyzaar (losartan + HCTZ) Micardis HCT (telmisartan + HCTZ) Teveten HCT (eprosartan + HCTZ)  Thiazide Combinations Thiazide + BB Corzide (nadalol [NS] + bendoflumethiazide) Dutoprol, Lopressor HCT (metoprolol [S] + HCTZ) Tenoretic (atenolol [S] + chlorthalidone) Ziac (bisoprolol [S] + HCTZ) Thiazide + DRI Tekturna HCT (aliskiren + HCTZ) Thiazide + K+-sparing Dyazide, Maxzide (triamterene + HCTZ) diuretic  Loop Diuretics Loop diuretics inhibit the Na+/K+/2Cl- symporters in the thick ascending limb of the loop of Henle. They can lead to electrolyte and volume depletion more readily than the thiazides and have a much shorter duration of action. When a loop diuretic is given twice daily, the acute diuresis can be excessive and lead to more side effects associated with hypovolemia than occur with slower-acting, milder thiazide diuretics. Therefore, they are generally NOT used for treating HTN except in the presence of renal dysfunction or edematous heart failure.  Loop Diuretics Common adverse effects of loop diuretics include: hypokalemia hyponatremia hypocalcemia ototoxicity (loop diuretics can cause dose- related hearing loss that is may or may not reversible) GI disturbances (nausea, anorexia, vomiting, diarrhea) Loop diuretics are more common for the treatment of edema and the maintenance of renal function (when it's in a state of decline) than for the treatment of hypertension. Bottom Line – Loop diuretics are not used frequently  K+-Sparing Diuretics / Aldosterone Receptor Blockers These drugs are seldom used alone; they are not very efficacious anti-hypertensive drugs when used as monotherapy. However, they are used in combination with a thiazide diuretic, mainly to counteract thiazide-induced potassium loss. Their modest anti-hypertensive actions are additive (at least) to those of a thiazide diuretic.  K+-Sparing Diuretics / Aldosterone Receptor Blockers In terms of the aldosterone receptor antagonists, eplerenone is similar to spironolactone but has fewer endocrine side effects. Eplerenone has been found to cause regression of left ventricular hypertrophy in hypertensive patients and regression of microalbuminuria in patients with type 2 diabetes. These findings open the possibility of increased use of this drug in persons with these conditions.  ACE Inhibitors (ACEIs) The ability to reduce levels of angiotensin II with orally effective inhibitors of angiotensin converting enzyme (ACE) represents an important advance in the treatment of hypertension. Captopril (Capoten) was the first such agent to be developed for the treatment of hypertension (its gone now), and a whole host of others soon followed. Overall, ACE inhibitors are broadly effective in all patient groups, lack the  ACE Inhibitors (ACEIs) Examples – the "---pril" drugs Captopril (generic) Enalapril (Vasotec, Epaned) Lisinopril (Prinivil, Zestril) Quinapril (Accupril) Ramipril (Altace) Benazepril (Lotensin) Trandolapril (Mavik) Moexipril (Univasc) Fosinopril (generic)  ACE Inhibitors (ACEIs) Mechanism of action Inhibition of ACE in the lungs, which leads to decreased angiotensin II (A- II) synthesis Low levels of A-II lead to a decrease in TPR Total Peripheral Resistance (TPR): resistance in blood vessels that the heart has to push against to move blood through your body by promoting High TPR = narrow vessels (makes the heart work harder) Low TPR = wider vessels, makes it easier for the blood to flow vasodilation and  ACE Inhibitors (ACEIs) Mechanism of action Inhibition of ACE also leads to increased bradykinin, a compound that also is a vasodilator  ACEI Combinations ACEIs are available in fixed dose combinations with thiazides (as mentioned earlier) and CCBs. ACEI + CCB combinations include: Amlodipine + benazepril (Lotrel) Verapamil + trandolapril (Tarka)  ACEIs – Adverse Effects Hyponatremia Due to increased Na+ excretion Dry irritating cough Thought to be associated with elevated kinin levels It's believed that ACE stimulates kininase, which degrades bradykinin and thereby regulates it's level in the circulation  ACEIs – Adverse Effects Hyperkalemia What is this due to??? What drug would you not want to combine an ACEI with? Fever, rashes, taste alterations Occurs in approx. 10% of patients; also likely associated with increased kinin levels Increased risk of renal failure Occurs in patients with bilateral renal artery stenosis  ACEIs – Adverse Effects Angioedema An infrequent, but serious and potentially fatal adverse effect (0.1-0.2% of patients) Manifested as dermal, subcutaneous or submucosal swelling involving the face, neck, lips, tongue, pharynx, larynx, hands, feet, genitalia, or viscera Associated with increased kinin levels  ACEIs – Precautions/Contraindications Severe hypovolemia can also occur after initial s of any ACE inhibitor in patients who are already hypovolemic due to diuretics, salt restriction or GI fluid loss. As a result, orthostatic hypotension can be a potential problem. ACE inhibitors should not be used during pregnancy and probably should be avoided in women of child-bearing age. There is increased risk of fetal injury and death that's thought to be associated with elevated kinin levels (particularly during nd rd  Unique Benefits of ACEIs 1. Increase cardiac output and survival in patients with heart failure 2. Increase survival in persons with MI and significant left ventricular dysfunction (a cardiac ejection fraction < 40%) 3. RENOPROTECTIVE EFFECT – particularly in diabetic patients who exhibit early signs of renal impairment (e.g., albuminuria and increased serum creatinine levels); studies indicate that the ACE inhibitors reduce the progression of diabetic nephropathy and the subsequent need for renal dialysis. Based on these findings, experts now recommend that an ACE inhibitor be given to diabetic patients with albuminuria or increased serum creatinine levels, regardless of whether they have Angiotensin Receptor Blockers (ARBs) The success of ACE inhibitors led to the development of ARBs. The ultimate outcomes are similar -- relaxation of vascular smooth muscle, increased Na+ and water excretion, and a reduction in blood volume. ARBs overcome some of the disadvantages of ACE inhibitors – they have no effect on bradykinin metabolism and therefore are more selective blockers of angiotensin effects than ACE inhibitors. Angiotensin Receptor Blockers (ARBs) Examples – the "---sartan" drugs Irbesartan (Avapro) Losartan (Cozaar) Valsartan (Diovan) Candesartan (Atacand) Olmesartan (Benicar) Eprosartan (Teveten) Telmisartan (Micardis) Angiotensin Receptor Blockers Mechanism of (ARBs) action Selectively block AT 1 receptors in various tissues and thereby reduce vasoconstrictio n, aldosterone secretion, and sodium/water reabsorption.  ARB Combinations ARBs are available in fixed dose combinations with thiazides (as mentioned earlier) and CCBs. ARB + CCB combinations include: olmesartan + amlodipine (Azor)  also Tribensor (+HCTZ) valsartan + amlodipine (Exforge)  also Exforge HCT telmisartan + amlodipine (Twynsta)  ARBs – Adverse Effects/Contraindications ARBs don't affect bradykinin metabolism, so they typically don’t carry as much risk for …… cough angioedema skin rashes, fever and taste alteration ARBs can, however, have the same electrolyte side effects (hyperkalemia, hyponatremia) as ACE inhibitors Like the ACE inhibitors, ARBs are also  Unique Benefits of ARBs Are they same as with the ACEIs ??? For the most part, the answer is YES, but long-term studies are still ongoing Direct Renin Inhibitors (DRIs) Aliskiren (Tekturna) was the first oral medication in a new class of antihypertensive agents, the direct renin inhibitors (DRIs) which were approved by the Food and Drug Administration in late 2007. Direct Renin Inhibitors (DRIs) Mechanism of action Binds to the active site of renin, preventing cleavage of angiotensinoge n and formation of AI and AII, thereby reducing vasoconstrictio  DRI Combinations DRIs are available in fixed dose combinations with thiazides (as mentioned earlier) and CCBs. The lone DRI + CCB combination came onto the market in late 2010: aliskirin + amlodipine (Tekamlo)  DRIs vs. ACEIs & ARBs Same side effect profile as ARBs (less risk for cough, angioedema, etc.) Also not recommended for use in pregnant females Benefits?  don’t know yet!  Calcium Channel Blockers (CCBs) In addition to their anti- anginal and anti-arrhythmic effects, CCBs also dilate peripheral arterioles and can exert cardiac depressant activity. The MOA in hypertension is inhibition of calcium influx into arterial smooth muscle cells and/or cardiac muscle and nodal cells.  Two Basic Types of CCBs Non-Dihydropyridines Block Ca+2 channels in vascular smooth muscle and cardiac muscle Examples include diltiazem (Cardizem LA; Dilacor XR) and verapamil (Calan, Covera HS) AND  Two Basic Types of CCBs Dihydropyridines --- the "---dipine" drugs Greater affinity for blocking vascular Ca+2 channels than for Ca+2 channels in the heart; hence, the dihydropyridines are more selective and potent as vasodilators and have less cardiac depressant effect than verapamil and diltiazem ….. But they can cause reflex tachycardia is some instances Examples (1st generation) – Nifedipine (Adalet CC, Procardia XL)  Two Basic Types of CCBs Dihydropyridines --- the "---dipine" drugs Examples (2nd generation) Amlodipine (Norvasc) Felodipine (Plendil) Isradipine (Dynacirc CR)  CCBs – Mechanism of Action By reducing calcium entry into vascular smooth muscle cells, peripheral vasodilation occurs which reduces TPR and, in turn, lowers blood pressure By reducing calcium entry into nodal cells and cardiac muscle cells, HR and SV decrease which reduces CO and, in  Calcium Channel Blockers (CCBs) Most of the CCBs used today are of the long- acting form Advantages  Do not cause dyslipidemias, glucose alterations or insulin resistance Do not affect sympathetic function No risk for hypovolemia Tend to work especially well in African-American patients  CCBs – Adverse Effects/Contraindications Verapamil and diltiazem should be combined very cautiously with beta-blockers because of their potential for depressing sinus node automaticity and ventricular contractility; they are never combined in patients who have conduction disturbances (e.g. – 2 or 3 degree AV block) or heart failure with marked systolic dysfunction The most common side effects are related to vasodilation -- headaches, dizziness, facial flushing, peripheral edema -- these tend to occur less with the slow release, long acting formulations (e.g. – amlodipine, Procardia XL) that have now become popular Constipation is occasionally seen, especially with The End