Unit 7 - Pharmacology PDF

System View: Drugs Affecting the Cardiovascular System Heart, blood vessels, and blood. Review: Hemodynamics Hemodynamics - study of the movement of blood throughout the circulatory system, along with the regulatory mechanisms and driving forces involved. Primary functions of the card...

System View: Drugs Affecting the Cardiovascular System Heart, blood vessels, and blood. Review: Hemodynamics Hemodynamics - study of the movement of blood throughout the circulatory system, along with the regulatory mechanisms and driving forces involved. Primary functions of the cardiovascular system: ○ Delivery of O2, nutrients, hormones, electrolytes, and other essentials to cells ○ Removal of CO2 and metabolic wastes from cells Distribution of blood in the cardiovascular system Adult - contains about 5L of blood. Large volume of blood in the venous system serves as a reservoir.  Blood moves within vessels because the force that drives flow is greater than the resistance to flow. In pharmacology, the most important determinant of resistance is vessel diameter. The larger the vessel, the smaller the resistance. Renin-Angiotensin- Aldosterone System (RAAS) - Determinant of blood pressure, activated when blood flow to the kidneys is decreased. Drugs: Antihypertensive Agents Angiotensin-Converting-Enzyme (ACE) Inhibitors benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), enalaprilat (Vasotec IV), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), trandolapril (Mavik). Therapeutic Actions and Indications Acts in the lungs to prevent ACE from converting angiotensin I to angiotensin II, a powerful vasoconstrictor and stimulator of aldosterone release. This leads to a decrease in BP and in aldosterone secretion. (slight increase in serum potassium and a loss of serum sodium and fluid) Indicated for the treatment of hypertension, alone or in combination with other drugs. Used in conjunction with digoxin and diuretics for the treatment of heart failure and left ventricular dysfunction. Pharmacokinetics All are administered orally. Can be given parenterally (enalaprilat) if oral use is not available or rapid onset is desirable. Well absorbed, widely distributed, metabolized in the liver, and excreted in the urine and feces. Have been detected in breast milk, are known to cross the placenta. Contraindications and Cautions Allergy Impaired renal function Caution in patients with heart failure, because the change in hemodynamics could be detrimental in some cases Pregnancy because of the potential for serious adverse effects on the fetus Lactation because of potential decrease in milk production and effects on the neonate. Adverse Effects Vasodilation and alterations in blood flow (reflex tachycardia, chest pain, angina, heart failure, cardiac arrhythmias) GI irritation, ulcers, constipation, and liver injury Renal insufficiency, renal failure, and proteinuria Rash, alopecia, dermatitis, and photosensitivity Clinically Important Drug-Drug Interactions: Allopurinol (xanthine oxidase inhibitors) - risk of hypersensitivity NSAID - risk of decreased antihypertensive effects Clinically Important Drug-Food Interactions: Absorption of oral ACE inhibitors decreases if they are taken with food. They should be taken on an empty stomach 1 hour before or 2 hours after meals. Drugs: Antihypertensive Agents Angiotensin II-Receptor Blockers The ARBs include the following drugs: azilsartan (Edarbi), candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), olmesartan (Benicar), telmisartan (Micardis), and valsartan (Diovan). Therapeutic Actions and Indications The ARBs are selectively bind with the angiotensin II receptors in vascular smooth muscle and in the adrenal cortex to block vasoconstriction and the release of aldosterone. These actions block the BP-raising effects of the RAAS and lower BP. Indicated to be used alone or in combination therapy for the treatment of hypertension and for the treatment of heart failure in patients who are intolerant to ACE inhibitors. Pharmacokinetics All are given orally Well absorbed and undergo metabolism in the liver Excreted in feces and in urine Cross the placenta Not known if they enter breast milk Contraindications and Cautions Allergy/hypersensitivity Caution should be used in the presence of hepatic or renal dysfunction, which could alter the metabolism and excretion of these drugs, and with hypovolemia, because of the blocking of potentially life-saving compensatory mechanisms. Pregnancy: candesartan, eprosartan, irbesartan, olmesartan, and telmisartan should not be used during the second or third trimester of pregnancy because of association with serious fetal abnormalities and even death when given in the second or third trimester; azilsartan, losartan, and valsartan should not be used at any time during pregnancy. Adverse Effects Headache, dizziness, syncope, and weakness, which could be associated with the drop in BP Hypotension GI complaints including diarrhea, abdominal pain, nausea, dry mouth, and tooth pain Symptoms of upper respiratory tract infections and cough Rash, dry skin, and alopecia Clinically Important Drug-Drug Interactions: If ARB is taken in combination with phenobarbital (anti-seizure), indomethacin (NSAID), or rifamycin (antibiotic) - risk of decreased serum levels and loss of effectiveness increases. There may be a decrease in anticipated antihypertensive effects if the drug is combined with ketoconazole (antifungal), fluconazole (antifungal), or diltiazem (antihypertensive-CCB). Drugs: Antihypertensive Agents Calcium Channel Blockers Decrease BP, cardiac workload, and myocardial oxygen consumption The effects on cardiac overload also make them very effective in the treatment of angina. Immediate-release and sustained-release forms: Amlodipine (Norvasc), felodipine (Plendil), isradipine (DynaCirc, DynaCirc CR), nicardipine (Cardene, Cardene SR) Others: nifedipine (Procardia XL), Clevidipine (Cleviprex) - IV Therapeutic Actions and Indications Inhibit the movement of calcium ions across the membranes of myocardial and arterial muscle cells, altering the action potential and blocking muscle contraction. This effect depresses myocardial contractility, slows cardiac impulse formation in the conductive tissues, and relaxes and dilates arteries, causing BP fall and a decrease in venous return. Pharmacokinetics Given orally Well-absorbed , metabolized in the liver, and excreted in the urine Can cross the placenta and enter breast milk Nicardipine and clevidipine are available in an IV form for short-term use when oral administration is not feasible. Contraindications and Cautions Allergy Heart block or sinus syndrome which could be exacerbated by the conduction-slowing effects of these drugs Renal or hepatic dysfunction which could alter the metabolism and excretion of these drugs C/I with pregnancy unless the benefit to the mother clearly outweighs any potential risk to the fetus because of the potential for adverse effects on the fetus or neonate. Adverse Effects CNS - dizziness, lightheadedness, headache, and fatigue GI - nausea, hepatic injury Cardiovascular - hypotension, bradycardia, peripheral edema, heart block Skin flushing, rash Clinically Important Drug-Drug Interactions: A potentially serious effect to note is an increase in serum levels and toxicity of cyclosporine (steroid-sparing immunosuppressant) if taken with diltiazem Clinically Important Drug–Food Interactions: The calcium channel blockers are a class of drugs that interact with grapefruit juice. When grapefruit juice is present in the body, the concentrations of calcium channel blockers increase, sometimes to toxic levels. Drugs: Antihypertensive Agents Vasodilators If other drug therapies do not achieve the desired reduction in BP, use a direct vasodilator. Most are reserved for use in severe hypertension or heypertensive emergencies. hydralazine (Apresoline), minoxidil (Loniten), nitroprusside (Nitropress) Therapeutic Actions and Indications Act directly on vascular smooth muscle to cause muscle relaxation, leading to vasodilation and drop in BP. They do not block the reflex tachycardia that occurs when BP drops. Indicated for the treatment of severe hypertension that has not responded to other therapy. Pharmacokinetics Nitroprusside - IV Hydralazine - oral, IV, IM Minoxidil - oral Rapidly absorbed and widely distributed Metabolized in the liver and primarily excreted in urine Cross placenta and enter breast milk Contraindications and Cautions Allergy Cerebral insufficiency - exacerbated by a sudden fall in BP Caution in patients with peripheral vascular disease, CAD, heart failure, or tachycardia - all of which could be exacerbated by the fall in BP Pregnancy - unless the benefit to the mother clearly outweighs the potential risk because of the potential for adverse effects on the fetus or neonate Adverse Effects Dizziness, anxiety, headache Reflex tachycardia, heart failure, chest pain, and edema Skin rash and lesions GI upset, nausea, and vomiting Cyanide toxicity (nitroprusside) - dyspnea, headache, vomiting, dizziness, ataxia, loss of consciousness, imperceptible pulse, absent reflexes, dilated pupils, distant heart sounds, and shallow breathing Thiosulfate is often administered concurrently with sodium nitroprusside to help detoxify cyanide. Hypothyroidism - suppression of iodine uptake Drugs: Other Antihypertensive Agents Diuretic Agents Drugs that increase the excretion of sodium and water from the kidney. First agents tried in mild hypertension Thiazide and thiazide-like diuretics - metolazone (Mykrox, Zaroxolyn), chlorothiazide (Diuril, hydroflumethiazide (Saluron) Potassium-sparing diuretics - amiloride (Midamor), spironolactone (Aldactone), triamterene (Dyrenium) Drugs: Other Antihypertensive Agents Renin Inhibitor Aliskiren (Tekturna) - inhibits renin, leading to plasma renin activity and inhibiting the conversion of angiotensinogen to angiotensin I. This inhibition of RAAS leads to decreased BP, decreased aldosterone release, and decreased sodium reabsorption. Drugs: Other Antihypertensive Agents Sympathetic Nervous System Blockers Drugs that block the effects of the sympathetic nervous system are useful in blocking many of the compensatory effects of the sympathetic nervous system. A. Beta-blockers - block vasoconstriction, decrease heart rate, decrease cardiac muscle contraction, inhibit release of renin. Atenolol (Tenormin), metoprolol (Lopressor), nebivolol (Bystolic), esmolol, propranolol (Inderal) The beta blockers have at least four useful actions in hypertension: 1. Blockade of cardiac beta 1 receptors decreases heart rate and contractility, thereby causing cardiac output to decline. 2. Can suppress reflex tachycardia caused by vasodilators. 3. Blockade of beta 1 receptors on juxtaglomerular cells of the kidney reduces release of renin and thereby reduces angiotensin II–mediated vasoconstriction and aldosterone-mediated volume expansion. 4. Long-term use of beta blockers reduces peripheral vascular resistance by a mechanism that is unknown. B. Alpha 1 blockers - used to treat hypertension because of their ability to block the postsynaptic alpha 1-receptor sites. This decreases vascular tone and promotes vasodilation, leading to a fall in blood pressure. doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin) The most disturbing side effect of alpha blockers is orthostatic hypotension. Drugs: Antihypotensive Agents If BP becomes too low, the vital centers in the brain and the rest of the tissues of the body may not receive sufficient oxygenated blood to continue functioning. Severe hypotension or shock puts the body in serious jeopardy; it is often an acute emergency situation, with treatment required to save the patient’s life. Drugs: Antihypotensive Agents Sympathetic Adrenergic Agonists or Vasopressors Sympathomimetic drugs are the first choice for treating severe hypotension or shock. dobutamine (Dobutrex), dopamine (Intropin), ephedrine (generic), epinephrine (Adrenalin, EpiPen), isoproterenol (Isuprel), norepinephrine (Levophed), phenylephrine (Neo-Synephrine) Therapeutic Actions and Indications React with sympathetic adrenergic receptors to cause the effects of a sympathetic stress response: increased BP, increased blood volume, and increased strength of cardiac muscle contraction. These actions increase BP and may restore balance to the cardiovascular system while underlying cause of shock is treated. Adverse Effects Decreased GI activity with nausea and constipation, increased RR and changes in BP, headache, and changes in peripheral blood flow with numbness, tingling, and even gangrene in extreme cases. Used with caution with any disease that limits blood flow, with tachycardia, or with hypertension. Drugs: Antihypotensive Agents Alpha-Specific Adrenergic Agents midodrine (ProAmatine) An alpha-specific adrenergic agent used to treat orthostatic hypotension - hypotension that occurs with position change that interferes with a person’s ability to function and has not responded to any other therapy. ProAmatine has been discontinued in the market. Therapeutic Actions and Indications Midodrine activates alpha-receptors in arteries and veins to produce an increase in vascular tone and an increase in blood pressure. It is indicated for the symptomatic treatment of orthostatic hypotension in patients whose lives are impaired by the disorder and who have not had a response to any other therapy. Adverse Effects The most common adverse effects associated with this drug are related to the stimulation of alpha-receptors and include piloerection, chills, and rash; hypertension and bradycardia; dizziness, vision changes, vertigo, and headache; and problems with urination.