Cardiovascular Pharmacology PDF

Cardiovascular pharmacology PHARMACOLOGY OF Anti-hypertensive and Anti-angina drugs & Drugs for heart failure...

Cardiovascular pharmacology PHARMACOLOGY OF Anti-hypertensive and Anti-angina drugs & Drugs for heart failure Newman Osafo, B.Pharm., Ph.D. Department of Pharmacology, FPPS, CoHS, KNUST. [email protected] 8/10/22 1 § Hypertension is a condition that afflicts almost 1 billion people worldwide and is a leading cause of morbidity and mortality. § More than one in four adults in Ghana have hypertension. This high prevalence has persisted for decades and is similar in rural and urban populations. Ø When the left ventricle ejects blood into the aorta, the aortic pressure rises. The maximal aortic pressure following ejection is termed the systolic blood pressure (SBP) Ø As the left ventricle is relaxing and refilling, the pressure in the aorta falls. The lowest pressure in the aorta, which occurs just before the ventricle ejects blood into the aorta, is termed the diastolic blood pressure (DBP) Ø Hypertension may be defined as an abnormal elevation of either SBP or DBP 8/10/22 2  *Arterial pressures less than 90/60 mmHg are considered 8/10/22 hypotension, and therefore not normal 3  Causes of HPT § The are two basic types of hypertension: I. Primary (essential) hypertension: Most patients (90-95%) have essential hypertension, which is a form with no identifiable underlying cause. Ø This form of hypertension is commonly treated with drugs in addition to lifestyle changes (e.g., exercise, proper nutrition, weight reduction, stress reduction). II. Secondary hypertension: A smaller number of patients (5-10%) have secondary hypertension that is caused by an identifiable underlying condition such as renal artery disease, thyroid disease, primary hyperaldosteronism, pregnancy, etc. Ø Patients with secondary hypertension are best treated by controlling or removing the underlying disease or pathology, although they may still require antihypertensive drugs Ø Some causes of secondary hypertension: Ø Renal artery stenosis Ø Chronic renal disease Ø Hyper- or hypothyroidism Ø Primary hyperaldosteronism Ø Pheochromocytoma Ø Stress Ø Pre-eclampsia 8/10/22 4 Hypertension More than one in four adults in Ghana have hypertension. This high prevalence has persisted for decades and is similar in rural and urban populations. Leads to MI, heart failure, stroke and renal disease Strong correlation with metabolic syndrome BP review Any condition that affects heart rate, stroke volume or peripheral vascular resistance affects arterial blood pressure Compensatory mechanisms to maintain balance between hypotension and hypertension BP review BP regulation operates in a negative feedback system Baroreceptors and chemoreceptors in the carotid arteries and aortic arch detect changes in arterial blood pressure and in pO2, pCO2 and H+. Increased BP results in increased stretch of vessels; activation of vagus and stimulation of medulla via sympathetic or parasympathetic pathways. BP review Normally, when the arterial blood pressure is elevated 1. Kidneys will excrete more fluid 2. Fluid loss will result in decreased ECF volume and blood volume 3. Decreased blood flow to the heart will reduce cardiac output 4. Decreased CO reduces arterial blood pressure 5. Vascular endothelium produces vasodilating substances (nitric oxide, prostacyclin) which reduce blood pressure Non-pharmacologic Management of Hypertension Weight reduction Exercise Salt restriction in diet Stress reduction Dietary Approach to Stop Hypertension (DASH) eating plan Moderation in alcohol intake If systolic BP cannot be maintained hypotension ü Urinary incontinence but associated with reflex tachycardia. ü Retention of salt and water ü Also used in BPH (decreasing tone of occurs when these drugs are urinary sphincter) administered without diuretics. § Good effect on lipid profile doxazosin (Cardura®) prazosin (Minipress®) terazosin (Hytrin®) 8/10/22 18 Beta blockers work upstream by decreasing renin release; decreases CO. Side effects Used with caution in ü Cardiovascular depression ü Asthma ü Sexual dysfunction ü Vasospastic disorder ü Fatigue ü Diabetes (masks ü Increases LDL and TGs (only in hypoglycaemia-induced patients with abnormal lipid profile) tachycardia) ü Depression, fatigue and decreased libido 8/10/22 19 Beta Adrenergic Blockers Decrease heart rate, force of myocardial contraction, cardiac output, and renin release from the kidneys Drugs of choice with patients with tachycardia, angina, MI, left ventricular hypertrophy and high renin hypertension Most are pregnancy category C and D  Propranolol The first β blocker shown to be effective in hypertension and ischemic heart disease. Now been largely replaced by cardioselective β blockers such as metoprolol and atenolol. β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure. Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β1receptors) 8/10/22 21 Toxicity: withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, and increased blood pressure. The withdrawal syndrome may involve up-regulation or supersensitivity of β adrenoceptors. 8/10/22 22 Others: Atenolol Esmolol Bisoprolol Metoprolol Carvedilol* Timolol Labetalol* 8/10/22 23 Calcium Channel Blockers Used: Angina Arrhythmia (verapamil and diltiazem) Hypertension 8/10/22 24 Calcium Channel Blocking Agents (CCBs) Useful in hypertension as dilate peripheral arteries and decrease peripheral vascular resistance by relaxing vascular smooth muscle Monotherapy or in combination Tolerated well in renal failure CCB Site of Action Verapamil (heart); Diltiazem (heart & vessels) Dihydropyridines (prototype: nifedipine Others; amlodipine, felodipine, isradipine, nicardipine, clevidipine) 8/10/22 26 CCB Action diltiazem & verapamil decrease automaticity & conduction in SA & AV nodes decrease myocardial contractility decreased smooth muscle tone decreased TPR nifedipine decreased smooth muscle tone decreased TPR All dihydropyridines are equally effective at lowering BP 8/10/22 Tocolytic 27 others Clevidipine (iv) Amlodipine Isradipine Nicardipine Felodipine 8/10/22 28 Side Effects of CCBs Cardiovascular hypotension, palpitations & tachycardia Increased MI risk and mortality in patients receiving short-acting nifedipine for HPT Gastrointestinal constipation & nausea (verapamil) Other Gingival hyperplasia (dihydropyridines) rash, flushing & peripheral edema 8/10/22 29  Renin-Angiotensin Aldosterone System Angiotensin II = vasoconstrictor Constricts blood vessels & increases BP Increases SVR or afterload ACE-I blocks these effects decreasing SVR & afterload 8/10/22 30  Direct renin inhibitors These drugs inhibit the rate limiting step of the RAAS. i.e. conversion of angiotensinogen to angiotensin. They interrupt the negative feed back effect of AII. Drugs in this class include Aliskiren. 8/10/22 31  ACE Inhibitors RAAS Angiotensin I. ACE Angiotensin II 1. potent vasoconstrictor - increases BP 2. stimulates Aldosterone - Na+ & H2O reabsorbtion 8/10/22 32  ACEIs Reverse remodeling of heart muscle and blood vessels Reno-protective Excellent for heart failure and hypertension Improve post-myocardial infarction survival Used alone or in combination  ACEIs Useful in heart failure as they decrease peripheral vascular resistance, cardiac workload and ventricular remodeling Captopril is the prototype Low incidence of side effects Can cause cough or hypotension when first started  ACEIs Can cause hyperkalemia Should never be used during pregnancy May not be as effective in African Americans—may add diuretic in this population to increase efficacy  ACE Inhibitors Aldosterone secreted from adrenal glands cause sodium & water reabsorption Increase blood volume Increase preload ACE-I blocks this and decreases preload 8/10/22 36  Angiotensin Converting Enzyme Inhibitors captopril (Capoten®) enalapril (Vasotec®) lisinopril (Prinivil® & Zestril®) quinapril (Accupril®) ramipril (Altace®) benazepril (Lotensin®) fosinopril (Monopril®) 8/10/22 37  Side effects ü Severe hypotension can occur after initial doses of any ACE ü acute renal failure ü Hyperkalemia ü dry cough sometimes accompanied by wheezing, and angioedema. ü Contraindicated in second and third trimester. ü Recent reports of teratogenicity in first trimester 8/10/22 38  Angiotensin II Receptor Blockers (ARBs) Block effects of angiotensin II, compete with angiotensin II for tissue binding sites Block the receptors in brain, kidneys, heart, vessels and adrenal tissue ARBs Similar end results as seen with ACEIs Less likely to cause hyperkalemia Persistence of cough is rare Prototype is Losartan  Angiotensin receptor blockers (ARBs) Azilsartan (Edarbi®) Candesartan (Atacand®) Losartan (Cozaar®) Olmesartan (Benicar®) Valsartan (Diovan®) Irbesartan (Avapro®) Telmisartan (Micardis®) Side effects similar to ACEI but cough and angioedema less common. 8/10/22 41  Diuretic Site of Action 8/10/22 42  Diuretics Useful in hypertension due to their sodium and water depletion May be used as monotherapy Preferred in the elderly and in African-Americans Should be included in any multi-drug regimen Thiazide diuretics are most used diuretics for hypertension Mechanism Water follows Na+ 20-25% of all Na+ is reabsorbed into the blood stream in the loop of Henle 5-10% in distal tubule & 3% in collecting ducts If it can not be absorbed, it is excreted with the urine ß Blood volume = ß preload ! 8/10/22 44  Side Effects of Diuretics electrolyte losses [Na+ & K+ ] Hypovolaemia Hyperurecemia (loop, thiazides) Myalgia Ototoxicity (ethacrynic acid>>> furosemide) N/V/D dizziness Hyperglycemia and hyperlipidaemia (thiazides) Sulphonamide hypersensitivity (CA inhibitors, Loop diuretics, thiazides) 8/10/22 45 Diuretics Osmotic diuretics Mannitol (Osmitrol®), Dorzolamide (Trusopt®) Carbonic anhydrase inhibitors Acetazolamide (Diamox®). Thiazides: Chlorothiazide (Diuril®) & Hydrochlorothiazide (HCTZ®, HydroDIURIL®) Loop (high ceiling) Diuretics Furosemide (Lasix®), Bumetanide (Bumex®), Ethacrynic acid (Edecrin®) Potassium Sparing Diuretics Spironolactone (Aldactone®), Eplerenone (Inspra®), Amiloride (Midamor®), Triamterene (Dyrenium®). 8/10/22 46 Thiazide Diuretics Chemically related to sulfonamides so caution with sulfa allergies Used in long term management of heart failure and hypertension Affect distal convoluted tubule Effectiveness decreases as the GFR decreases. Ineffective when GFR is < 30 mL/minute. As rising creatinine noted, should use alternative such as loop diuretic. Thiazide Diuretics Chlorothiazide Chlorthalidone Hydrochlorothiazide Loop Diuretics Inhibit sodium and chloride reabsorption in the ascending limb of the Loop of Henle Potent diuresis Need to restrict dietary sodium when taking these meds Furosemide is the prototype Loop Diuretics Bumetamide more potent than Furosemide Can be given either as oral agents, IV or IM Rapid administration can cause deafness Must monitor potassium levels, also weight would be optimum Potassium Sparing Diuretics Act at distal tubule to decrease reabsorption of sodium and potassium excretion Spironolactone (prototype) blocks the sodium retaining effects of aldosterone Weak diuretics when used alone, often used in combination Contraindicated in renal failure  Osmotic Diuretics Produce rapid diuresis by increasing the solute load of the glomerular filtrate Water is pulled into the intravascular space and excreted via kidneys Useful in managing oliguria or anuria Can prevent acute renal failure during prolonged surgery, trauma or during chemotherapy Osmotic Diuretics Help reduce increased ICP, reduction of intraocular pressure before certain ophthalmic surgery and for urinary excretion of toxic substances Examples include mannitol, isosorbide and glycerin  Vasodilators Directly relaxes arteriole smooth muscle Decrease SVR = decrease afterload Vasodilation of veins and arteries decreases cardiac work and cardiac oxygen consumption to relieve the pain of myocardial ischemia Nitrites and nitrates may cause a drop in blood pressure and reflex tachycardia These drugs can be used to treat acute attacks of angina or to prevent anginal attacks 8/10/22 54 Vasodilators Relax smooth muscle in blood vessels resulting in dilation and decreased peripheral vascular resistance Reduce afterload so helpful in heart failure May cause sodium and water retention Limited effect when used alone. Vasodilating action that lowers BP also stimulates SNS. This, in turn, triggers reflexive compensatory mechanisms that raise BP  Ethnic Considerations Use calcium channel blockers, diuretics and alpha blockers most effective in African Americans; beta blockers, ACEIs and some ARBs are not as effective as in Caucasians Beta blockers have greater effects on Asians than in Caucasians  Adverse Effects of Nitrites and Nitrates Vasomotor flushing, dizziness, and headache are common due to vasodilation Hydralazine – Systemic lupus erythematous (SLE)-like syndrome in slow acetylators – When administered for acute angina, the sudden onset of vasodilation may cause hypotension, fainting, and tachycardia. v Used in managing HPT in pregnancy. sodium nitroprusside (Nipride®) – Cyanide toxicity in renal failure hence not given for more than 24-36 h at a time. – CNS toxicity = agitation, hallucinations, etc. Patients should be seated when inhaling or taking these drugs sublingually 8/10/22 57 Drugs acting to open Potassium channels Minoxidil and Diazoxide ü Open ATP-dependent K+ channels causing hyperpolarization of smooth muscles resulting in arteriolar vasodilation ü Used in hypertensive emergencies (Diazoxide) ü Severe HPT (Minoxidil) ü Baldness (topical minoxidil) § Side effects ü Increased hair growth (hypertrichosis)- minoxidil, hyperglycaemia- diazoxide, oedema, reflex tachycardia 8/10/22 58  Hypertensive Emergencies Is defined as having end organ damage or diastolic BP of 120 mmHg or higher With oral medications, use captopril 25-50 mg po every 1 to 2 hours or clonidine , 0.2 mg initially then 0.1 mg every hour until diastolic blood pressure falls below 110 mmHg or 0.7 mg has been given  Hypertensive Emergencies Nitroglycerine—tolerance develops over 24-48 hours Nitroprusside—intra-arterial blood pressure should be monitored; metabolized to thiocyanate (precursor to cyanide), a toxic metabolite. Measure serum levels if drug given over 72h. Is photosensitive. Fenoldopam — IV infusion, use short term.  Pharmacology Of Drugs for Pulmonary Artery Hypertension 8/10/22 61  Pulmonary hypertension is abnormally elevated pressure in the pulmonary circulation. Pulmonary hypertension can have no identifiable cause (idiopathic) Pulmonary hypertension can be caused by certain drugs, diseases (scleroderma, dermatomyositis, systemic lupus), infections (HIV, schistosomiasis), liver disease, valvular heart disease, congenital heart disease, chronic obstructive lung disease (COPD), blood clots in the lungs, and persistent pulmonary hypertension of the newborn (PPHN). Risk factors for pulmonary hypertension are liver failure, chronic lung disease, blood clotting disorders, and underlying diseases, such as scleroderma, dermatomyositis, and systemic lupus erythematosus. 8/10/22 62  Sildenafil (Revatio) An inhibitor of type V PDE Increases cGMP, relaxing pulmonary arteries Epoprostenol (Flolan) Potent peripheral vasodilator of all vascular beds Administered via infusion pump Bosentan (Tracleer) Competitive antagonist of endothelin-1; blocks endothelin receptors on vascular endothelium and smooth muscle. Orally administered 8/10/22 63  Pharmacology Of Anti-anginal drugs 8/10/22 64 Angina Angina occurs when there is an INBALLANCE between O2 requirements of the heart cells (myocardial O2 demand) and O2 available to it (myocardial O2 supply). i.e. In angina, Coronary blood supply is insufficient to meet the myocardial energy requirements Three types: Stable, Unstable & Variant Angina 8/10/22 65 Stable angina § Attacks are provoked by exertion or excitement. § The attack ceases when the increased energy demand is withdrawn. § The underlying pathology is usually chronic coronary artery disease. § Treatment could be directed at increasing myocardial O2 supply through vasodilation § or reducing myocardial O2 consumption through reduced heart rate, decreased myocardial contractility, decreased preload and decreased afterload 8/10/22 66  Variant angina/Atypical angina § It occurs when the increase in myocardial O2 demand is due to spasms of the coronary arteries as in coronary artery stenosis 8/10/22 67 Unstable angina o The underlying pathology for unstable angina is usually rapture of an atheromatous plaque with thrombus formation in a coronary artery. o Coronary spasms may be an additional mechanism. o Unstable angina may lead to myocardial infarction and/or sudden death. § It occurs with lesser exertion or at rest § It is unpredictable, unlike stable angina 8/10/22 68  § Drugs that are used for treating or preventing attacks of angina include: § Organic nitrates § Ca2+ channel blockers § b blockers § & K+ channel activators: nicorandil § Selective pacemaker I(f)- inhibitors: Ivabradine 8/10/22 69  § In Unstable angina, other useful pharmacological agents include: § Low dose aspirin and other antiplatelet such as Clopidogrel, Ticlopidine and dipyridamole § Anticoagulants such as heparin, warfarin and heparin derivatives (e.g Enoxaprin) § Lipid lowering drugs e.g the Simvastatin, Atorvastatin, Rosuvastatin, etc § Anti-thrombolytics 8/10/22 70  PHARMACOLOGY OF Drugs for the Failing Heart 8/10/22 71  heart failure Inability of the ventricles to pump enough blood to meet metabolic demands Not a distinct disease – associated with several disorders No cure for Heart failure (HF): prevent, treat & remove underlying cause. Effective drug treatment removes symptoms & prolong life. 8/10/22 72  Non-Pharmacological Therapy In early stages stop smoking & limit alcohol limit sodium intake – food rich in k+ & Mg2+ exercise plan understand how to reduce stress reduce weight to optimal limit caffeine 8/10/22 73 8/10/22 74 8/10/22 75  drug classes for HF 1. Cardiac Glycosides 2. Angiotensin Converting Enzyme Inhibitors 3. Vasodilators & Diuretics 4. Beta- Adrenergic Blockers (carvedilol, metoprolol, bisoprolol) 5. Angiotensin receptor-Neprilysin inhibitor 6. Phosphodiesterase (PDE) Inhibitors 7. If-channel inhibitor 8/10/22 76  PDE INHIBITORS Used for short-term management of heart failure or long-term management for patients awaiting a transplant. Include the drugs inamrinone lactate (Inocor) and milrinone (Primacor). 8/10/22 77  Pharmacokinetics: Both drugs are administered IV; distributed rapidly; metabolized by the liver; excreted by the kidneys. Pharmacodynamics: Improve cardiac output by strengthening contractions by moving calcium into the cardiac cell. Pharmacotherapeutics: Used for the management of heart failure when patients haven’t responded adequately to treatment with dig, diuretics, or vasodilators. 8/10/22 78 PDE INHIBITORS Drug interactions: Because they reduce serum potassium levels, when taken with potassium-wasting diuretics may cause hypokalemia. Adverse reactions: Uncommon but the risk increases with prolonged use (arrhythmia, thrombocytopenia) 8/10/22 79  Angiotensin receptor-Neprilysin inhibitor (ARNi) It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, in a 1:1 mixture by molecule count. It is recommended for use as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction (HFrEF). Neprilysin is a neutral endopeptidase and its inhibition increases bioavailability of bradykinin. 8/10/22 80  If channel inhibitor Ivabradine acts on If channel in sinus node and slows the heart rate in patients with sinus rhythm. Ivabradine is recommended in stable patients or those who are intolerant to BB to reduce HF hospitalization and mortality. However, Ivabradine therapy may increase the risk of atrial fibrillation development. 8/10/22 81  Treatment Not Recommended in Heart Failure Diltiazem and verapamil pose negative inotropic effect on heart function and increase the risk of HF worsening thus not recommended in patients with HFrEF. Alpha-adrenoceptor antagonist causes neurohormonal activation, fluid retention and deteriorate heart function and is not recommended in patients with HFrEF 8/10/22 82 Use of anti-hypertensives in comorbid conditions Indication Suitable drug(s) Angina CCBs, Beta blockers Heart failure ARBs, ACEIs, beta blockers BPH Alpha blockers Dyslipidaemia Alpha blockers, CCBs, ACEIs, ARBs Post-MI Beta blockers Diabetes ARBs, ACEIs 8/10/22 83