NMT150 Pharm Wk12 Spotlight Antihypertensive Drugs PDF

ANTIHYPERTENSIVE DRUGS Dr. Adam Gratton NMT150 MSc ND March 27 and 30, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to treat hypertension - Angiotensin converting enzyme inhibitors - Angiotensin recept...

ANTIHYPERTENSIVE DRUGS Dr. Adam Gratton NMT150 MSc ND March 27 and 30, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to treat hypertension - Angiotensin converting enzyme inhibitors - Angiotensin receptor blockers - Direct renin inhibitors - Alpha blockers - Beta blockers - Calcium channel blockers - Centrally acting sympatholytics - Diuretics INTRODUCTION Hypertension is the leading cause of death or disability globally Approximately 23% of Canadian adults have a diagnosis of hypertension Blood pressure targets are reached in approximately 65% of those with a diagnosis Control in women has decreased over the last ten years and is now under 50% INTRODUCTION Regulation of blood pressure is complex and controlled by several physiological systems Two major drivers of elevated blood pressure are obesity (primarily in younger adults) and vascular stiffness (primarily in older adults) Commonly considered a risk factor for future cardiovascular sequelae, like stroke, myocardial infarction, heart failure, chronic kidney disease, and dementia RENIN-ANGIOTENSIN- ALDOSTERONE DRUGS Short and long-term control of blood volume is determined by the kidneys using blood pressure and fluid volume as the driving force Drug classes include: angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists (ARB), direct renin inhibitors ACE INHIBITORS Exemplar drug: Quinapril Generic naming convention: -pril Binds the zinc atom at the active site of ACE and prevents angiotensin I from accessing it inhibiting production of angiotensin II Angiotensin II is a potent vasoconstrictor and acts at the adrenal cortex to release aldosterone ACE INHIBITORS Decreases both arterial and venous pressure, which reduces cardiac afterload and preload, respectively Prevention of compensatory increase in sodium retention that can occur with other drugs that reduce blood pressure Renal sodium retention is decreased, therefore renal potassium retention is increased (serum potassium levels typically increased by ~0.5mEq/L) ACE is also involved in the metabolism of bradykinin QUINAPRIL Food reduces absorption by 25-30%, particularly with high-fat meals Like many ACEi it is administered in prodrug form Long-lasting effects permitting once or twice daily dosing QUINAPRIL A member of a commonly used class of drugs for a number of diseases: Hypertension Diabetes Ischemic heart disease Post myocardial infarction Chronic kidney disease QUINAPRIL ADVERSE EFFECTS Dry cough is the most limiting adverse effect. If present, it usually forces the patient off of the medication as there is no effective way to manage it Hyperkalemia Angioedema (less often) Can precipitate renal failure in renovascular disease, volume depletion, or those receiving NSAIDs Not to be combined with potassium supplements or potassium-sparing diuretics QUINAPRIL All ACEi are contraindicated in pregnancy and caution should be used if the patient could become pregnant Low doses (50% of initial dose) should be used if the patient is also on a diuretic Renal function and potassium levels should be monitored regularly ANGIOTENSIN II RECEPTOR BLOCKERS Exemplar drug: candesartan Generic naming convention: -sartan In terms of use, they are very similar to ACEi Act as an antagonist and angiotensin II receptors and therefore block angiotensin II signalling which Inhibits vasoconstriction, aldosterone secretion and sodium reabsorption CANDESARTAN Identical adverse effects and contraindications as seen with ACEi (quinapril) All ARBs are contraindicated in pregnancy Indications are very similar to quinapril The primary difference between quinapril and candesartan is that since candesartan does not interfere with bradykinin metabolism reducing the potential to cause cough ARBs may have greater antihypertensive effects than ACEi Combining ACEi and ARB is not recommended DIRECT RENIN INHIBITOR Exemplar drug: aliskiren Binds to the active site of renin which prevents cleavage of angiotensinogen and therefore inhibits formation of angiotensin I (and II) ALISKIREN Incidence of cough and hyperkalemia is low compared with ACEi or ARB Most common adverse effect is diarrhea Not to be combined with ACEi or ARB Contraindicated in pregnancy and use is cautioned in those that can become pregnant It is a fairly new drug so long term safety data is lacking CALCIUM CHANNEL BLOCKERS All CCBs function as L-type calcium channel antagonists L-type calcium channels are expressed in cardiac myocytes, pacemaker cells and arteries In cardiac myocytes, L-type calcium channels permit calcium entry upon depolarization which activates ryanodine receptors in the sarcoplasmic reticulum releasing stored calcium (calcium-induced calcium release) resulting in muscular contraction  CALCIUM CHANNEL BLOCKERS In pacemaker cells, like the sinoatrial node, L-type calcium channels are involved in the steep depolarization phase of the action potentials generated there CALCIUM CHANNEL BLOCKERS Dihydropyridine: amlodipine More affinity for L-type calcium channels in the vasculature Non-dihydropyridine Phenylalkylamine class: verapamil More affinity for L-type calcium channels in the heart Benzothiazepine class: diltiazem Affinity for L-type calcium channels in both vasculature and the heart CALCIUM CHANNEL BLOCKERS Why 2 different classes? Dihydropyridines, being selective for the vasculature, have the tendency to cause rebound tachycardia because of the pronounced vasodilation and hypotension Detrimental for ischemic diseases as this results in greater myocardial oxygen demand Since they don’t have the capacity to alter cardiac function they are better when cardiac function is compromised (like with heart failure) or when altering it is not needed (uncomplicated hypertension) CALCIUM CHANNEL BLOCKERS Nondihydropyridines have less affinity for the vasculature and therefore do not exhibit the rebound tachycardia and can be used in ischemic conditions or for arrythymias, due to their higher affinity for cardiac L-type calcium channels All three classes typically have short half lives (under 6 hours) and long acting formulations (sustained release) are generally used, particularly within the context of treating hypertension  CALCIUM CHANNEL BLOCKERS Drug Coronary Blood Heart Rate and AV Conduction Flow Contractility Velocity Amlodipine ↑↑ No change or No change or ↑(reflex) ↑(reflex) Diltiazem ↑↑ ↓ ↓ Verapamil ↑↑ ↓ or ↓↓ ↓ or ↓↓  Amlodipine Verapamil Diltiazem Ankle edema, Headache, dizziness, Headache, dizziness, bradycardia, flushing, headache, bradycardia, heart block, new heart block, new onset or worsening hypotension, onset or worsening of heart of heart failure tachycardia failure, constipation Inhibits metabolism of statins Inhibits metabolism of statins Additive inotropic effects with Additive negative inotropic effects beta-blockers and digoxin with beta blockers and digoxin Not recommended in patients Not recommended in patients with with heart failure or 2nd or 3rd heart failure or 2nd or 3rd degree heart degree heart block without a block without a functioning functioning pacemaker pacemaker SYMPATHOLYTIC DRUGS Essentially interfere with adrenergic signalling, either centrally (in the CNS) or peripherally Drug classes α-adrenoreceptor antagonists – prazosin β-adrenoreceptor antagonists – atenolol Centrally acting drugs - clonidine  ADRENERGIC RECEPTORS Alpha Receptors Beta Receptors α1 α2 β1 β2 Constriction Glucose Heart Smooth muscle of blood metabolism - Increases heart rate relaxation vessels (skin, Presynaptic - Increases impulse (respiratory tract, GI, kidney, regulation of conduction bladder, uterus) brain) NE - Increases force of Increases renin contraction release by Increases renin juxtaglomerular cells release from Glucose metabolism juxtaglomerular cells Lipolysis “ALPHA BLOCKERS” Exemplar drug: prazosin A selective α1-adrenoreceptor antagonist Inhibition of signalling results in decreased vasoconstriction which decreases peripheral resistance PRAZOSIN Indications: Primarily reserved for the treatment of hypertension that does not respond to other medications PRAZOSIN ADVERSE EFFECTS May cause reflex activation of the sympathetic nervous system which leads to increased heart rate, force of contraction, and circulating levels of NE (leads to increased myocardial oxygen requirements) Renal artery dilation leads to increased sodium and fluid retention Orthostatic hypotension, headache, drowsiness, palpitations, nasal congestion. “First dose” syncope (especially with diuretics) “BETA BLOCKERS” Generic naming convention: -lol Exemplar drug: atenolol Drugs within this class have varying affinities for β1 and β2 adrenergic receptors (some are more selective than others) Some also have some effect on α1 receptors Some also have the capacity to act as both agonist and antagonist at β1 receptors (dose-dependent) called intrinsic sympathomimetic activity ATENOLOL A selective β1 receptor antagonist This drug is primarily going to act on the heart to decrease heart rate, impulse conduction and force of contraction Also acts on juxtaglomerular cells inhibiting renin secretion which reduces angiotensin II and therefore reduces aldosterone Also appears to reduce sympathetic outflow from the CNS ATENOLOL Due to the many mechanisms and sites of action there are multiple indications Hypertension (not a first-line option) Heart failure Post myocardial infarction Coronary heart disease Arrhythmias ATENOLOL ADVERSE EFFECTS Fatigue, bradycardia, decreased exercise capacity, headache, impotence, and vivid dreams are common May also cause hyperglycemia, depression, heart failure, heart block May cause rebound hypertension with abrupt discontinuation ATENOLOL Not generally used as initial therapy May be appropriate for patients over the age of 60 Avoid use in patients with asthma Avoid in patients with severe peripheral arterial disease Contraindicated in patients with second- or third-degree heart block in the absence of a pacemaker CENTRALLY ACTING SYMPATHOLYTICS Exemplar drug: clonidine α2-adrenergic receptor agonist Stimulation of α2 receptors REDUCES sympathetic outflow from the CNS (brainstem) Reduced NE results in decreased peripheral resistance, heart rate, and blood pressure CLONIDINE Due to the fact it acts within the CNS it has much more potential for adverse effects than those that act in the periphery Adverse effects include: Sedation, dizziness, dry mouth, orthostatic hypotension Rebound hypertension with abrupt withdrawal CLONIDINE Not routinely used for cardiovascular diseases May potentially be used for hypertension during pregnancy Has many other indications for a wide variety of disorders where reducing in sympathetic activity would be desirable: treatment of substance withdrawal (nicotine, opioids, alcohol) ADHD DRUGS THAT REDUCE BLOOD VOLUME The diuretics can be split into categories based on the area in the nephron where they work Loop diuretics (Loop of Henle) Thiazide diuretics (distal convoluted tubule) K+ sparing diuretics (collecting duct) DIURETICS LOOP DIURETICS Drug: Furosemide Inhibition of Na/Cl/K symport Decreased sodium and potassium reabsorption in ascending loop Increased water excretion FUROSEMIDE Indications Mainly for anything that causes a lot of edema, such as heart failure, cirrhosis, pulmonary edema Can be used to treat hypertension and hypercalcemia but not routinely used for this purpose FUROSEMIDE Has the greatest potential to cause diuresis of all the diuretic classes Also increase magnesium and calcium excretion May cause ototoxicity Other adverse effects include: major electrolyte imbalances, blood cell deficiencies, increased cholesterol, glucose, or uric acid, and photosensitivity FUROSEMIDE Diuretic effect is decreased by NSAIDs Combination with ACEi may cause excessive hypotension The only diuretic class that can be used when renal function is substantially decreased THIAZIDE DIURETICS Drug: Hydrochlorothiazide Inhibition of Na/Cl symport Decrease Na reabsorption Increased water excretion HYDROCHLOROTHIAZIDE Typically the diuretic of choice for hypertension Seems particularly effective in African-American populations and the elderly Leads to calcium retention and may be helpful when a patient also has osteoporosis or nephrolithiasis Patient must have sufficient renal function for the drug to work HYDROCHLOROTHIAZIDE Particularly effective in patients with isolated systolic hypertension More effective in elderly and black patients HYDROCHLOROTHIAZIDE Adverse effects Leads to marked potassium and magnesium excretion Common: Hypotension, weakness, muscle cramps, impotence, hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia. Drug Interactions NSAIDs reduce the hypotensive effect Reduced efficacy of antihyperglycemic drugs POTASSIUM SPARING DIURETICS Drug: Spironolactone Inhibition of downstream effects of aldosterone binding to nuclear mineralocorticoid receptor Aldosterone stimulates sodium reabsorption and potassium excretion Inhibition blocks this, resulting in sodium excretion and potassium reabsorption SPIRONOLACTONE Minimal use within the context of cardiovascular disease May be used in combination with a thiazide or loop diuretics to prevent hypokalemia and hypomagnesemia in patients being treated for heart failure Adverse effects Antiandrogenic effects (which is why it’s sometimes used for acne) can cause gynecomastia SPIRONOLACTONE Drug Interactions ACEi, ARBs, potassium supplements NSAIDs reduce the diuretic effect SUMMARY OF DIURETICS Thiazide diuretics are first-line therapy for uncomplicated hypertension Loop diuretics are only really valuable when the patient is experiencing significant edema, which often occurs with heart failure TREATMENT STANDARDS For patients with hypertension and the absence of other comorbidities, a thiazide diuretic, beta-blocker, ACEi, ARB, or long-acting calcium channel blocker are all considered first-line therapy depending on patient factors For patients with hypertension and diabetes with additional risk factors, an ACEi or ARB should be started first SAMPLE QUESTION Which of the following antihypertensive drugs works by modifying the renin-angiotensin-aldosterone system? A. Atenolol B. Candesartan C. Clonidine D. Amlodipine SAMPLE QUESTION Which of the following antihypertensive drugs is considered first-line therapy for a hypertensive patient with type 2 diabetes who smokes one pack of cigarettes per day? A. Atenolol B. Hydrochlorothiazide C. Amlodipine D. Candesartan