Pharm and Med Sheet PDF

Hypertension Circulatory system - Systemic = the body vs. pulmonary = lungs - Purpose: a transit system for nutrients, oxygen, waste products - Blood flow is dependent on volume and pressure - Pressure within the arterial system is measured for blood pressure - Layers out to in:...

Hypertension Circulatory system - Systemic = the body vs. pulmonary = lungs - Purpose: a transit system for nutrients, oxygen, waste products - Blood flow is dependent on volume and pressure - Pressure within the arterial system is measured for blood pressure - Layers out to in: - tunica externa (collagen and elastic fibers) - tunica media (smooth muscle) - tunica intima (inner coat, elastic membrane - connective, endothelial) - Lumen Smooth muscle in blood vessels - Present in tunica media - Responds to hormonal and nervous system - Depolarization relies on extracellular calcium - SNS activity via receptors - Alpha-adrenergic receptors - excite (constrict) - Beta-adrenergic receptors - inhibit (dilate) Blood pressure - Blood volume - Smooth muscle elasticity - Cardiac output - Peripheral vascular resistance - Alterations in determinants produce abnormal pressures Nervous system mechanism - Controls centers in the medulla and pons - Baroreceptors - Pressure-sensitive receptors in carotid artery and aortic arch respond to changes in vessel wall stretch - Modify HR and vasoconstriction - Arterial chemoreceptors - Cells in carotid artery and aortic arch are sensitive to levels of O2, CO2, H ions - Cells regulate respiration and vasoconstriction Hormonal mechanism - Renin-angiotensin-aldosterone system (RAAS) - Multiple enzymes affecting vascular tone - Multiple antihypertensive medications affect system - Vasopressin - ADH from posterior pituitary gland - Affects vasoconstriction - Epinephrine-norepinephrine - Modifies BP by HR and myocardial contractility Dyslipidemia - Condition of imbalance of triglycerides, phospholipids and total cholesterol less than 200 Low density lipoproteins (LDL) “bad” - 60 high ; are transformed to macrophages - Macrophages release free radicals -> oxidize LDL (toxic to endothelium) - Macrophagen ingest oxidized LDL -> foam cells - WBC, platelets, vascular endothelium release chemicals that promate plaque formation - Plaque blocks arteries Clinical manifestation of atherosclerosis - Has no manifestations until blood flow is disrupted - Unstable plaques have thin fibrous caps - Plaque can rupture and form clots (thrombus) - May completely block artery - May break free and become an embolus - S/S with severe narrowing or obstruction dependent on site ( heart, brain, kidney, lower extremities) Peripheral alertial disease (PAD) - Affects large perpharil arteries ( nor coronary, aortic arch, brain) - Manifestations - S/S are gradual - Primary symptoms = intermittent claudiacatio (pain with walking) - Atrophic changes, thinning skin and tissues of lower legs, decreased size in leg muscle, foot/feet cool  - Diagnosis - Physical assessment, ultrasound, CT, MRI, angiography Vasculitis Thromboangiitis Obliterans (TAO) or Berger’s disease - Recurring and progressive disorder causing thrombus formation - Younger (180/120 mmHg) that can damage target organs or cause death Orthostatic HTN - Decrease in BP when upright position is taken - Cause = a shifting of blood volume to lower extremities with lack of response by circulatory reflexes to maintain cerebral circulation - causes= aging, dehydration/reduced blood volume, physical decondtioning (prolonged rest), medications, autonomic nervous system dysfunction - Manifestations = weakness, nausea, dizziness, blurry vision, syncope; risk of falling  - Diagnosis = physical assessment including postural BP - trX= treat the cause (medications, hydration), wear compression hose, address fall risk Basic considerations for medication therapy - Benefits of lowering BP - Patient evaluation - HTN with treatable cause - Factors that increase cardiovascular risk - Diagnositc test - TrX goals - based on target BP Lifestyle modifications - Na+ restriction - DASH diet - Alcohol restriction - Aerobic exercise - Smoking cessation - Maintenance of K+ and calcium intake Pharmacologic therapy - Principal determinants of BP - Arterial pressure = cardiac output X peripheral resistance - Cardiac output = HR, myocardial contractility, blood volume, venous return - System that help regulate BP; sympathetic baroreceptor reflex, renin-angiotensin-aldosterone system, renal regulation of BP Classes of anti-HTensive Drugs - Dieuterics - Thiazide diuretics - High-ceiling (loop) diuretics - furosemide - Potassium-sparing diuretics - Sympatholytics (antiadrenergic drug) - Beta-adrenergic blockers - Alpha 1 blockers - alpha/beta-blockers: Carvedilol and labetalol - Central acting alpha1 agonist - Adrenergic neuron blockers - Direct-acting vasodilators: hydralazine and minoxidil - Calcium channel blockers - Drugs that suppress the renin-angiotensin-aldosterone system (RAAS) - ACE inhibitors - Angiotensin II receptor blockers - Aldosterone antagonist - Direct renin inhibitors Fundamentals of HTN drug therapy - Treatment algorithm using national guidelines - Initial drudge selection based on: - Patients without compelling indications  - Patients with compelling indications ( heart failure, diabetes) - Adding drugs to the reginmen if BP is not controlled - Rationale - should come for different clas for different mechanism of action - Benefits of multidurg therapy - more effective, lower doses - Dosing - low and slow - Step-down therapy - attemtp to reduce dose after one year Individualizing therapy - Patients with comorbid conditions - Renal disease - ACE and angiotensin-receptor blockers (ARBs) preferred - Diabetes - Patient in special populations - Af Amer. - HTN presents earlier and more severely; need to treat for better outcomes - Children and adolescents - secondary HTN rates higher in this population; treatment is requires - Elderly - HTN often present in those over 65; treatment decreases incdidence of heart failure and stroke Additional infor - Minimizing adverse effects (AE) - Asses medical history - Begin therapy “low and slow” - Promote adherance - Educate patient - Teach self-monitoring - Minimize SE - Establish collaborative relationship - Simplify the regimen - Other measures - family involvement, positive reinfroment Physiology of RAAS - renin is released from the kidney in response to decrease in BP, blood volume, Na+ levels and renal perfusion - Renin catalyzes the formation of angiotensin I from angiotensinogen - Angiotensin I is converted to antogiotesin II by ACE - Aldosterone is released by the adrenal cortex to cause Na+ retention (increases blood volume and therfrore BP) - Regulation of BP by the renin-angiotensin-aldosterone system - Helps regulate BP in the presence of hemorrhage, dehydration or Na+ depletion - Acts in 2 ways - Constricts renal blood vessels - Acts on kidney to promote retention of Na+ and H2O and excretion of K+ Angiotensin II Effects on Blood Pressure: 1. Raises blood pressure by: - Acting on the distal nephron to increase sodium reabsorption. - Enhancing vasoconstriction through: - Releasing norepinephrine from sympathetic nerves. - Releasing epinephrine from the adrenal medulla. - Stimulating the central nervous system to increase sympathetic outflow. Blood Pressure Regulation Pathway: - Starting Point: Angiotensinogen, converted to angiotensin I by renin (stimulated by low BP, low blood volume, low renal perfusion, sodium depletion, beta1 stimulation). Renin is blocked by direct renin inhibitors. - Conversion Step: Angiotensin I (inactive) is converted to angiotensin II (active) by ACE, which is blocked by ACE inhibitors. - Pathways to Increased Blood Pressure: 1. Vasoconstriction Pathway: Systemic vasoconstriction (arterioles and veins) raises blood pressure; blocked by ARBs. 2. Aldosterone Pathway: Aldosterone release leads to sodium and water retention (increasing blood volume) and potassium loss; blocked by ARBs and aldosterone antagonists. 3. Renal Vasoconstriction Pathway: Reduced renal blood flow decreases glomerular filtration, leading to sodium and water retention, potassium loss, and increased blood volume. Angiotensin-converting enzyme (ACE) and kinase II are two names for the same enzyme. When the enzyme acts on angiotensin II, it's called ACE; when it acts on bradykinin, it's called kinase II. Inhibiting this enzyme reduces angiotensin II levels (by lowering its production) and raises bradykinin levels (by slowing its breakdown). Mechanism of action/ pharmacologic effects - Reduced levels of angiotensin II - dilated blood vesslels, reduces blood volume - Increases levels of bradykinin - vasodilator (can promote cough and angioedema) Pharmacokinetics - Absorption - majority oral administration; can be with food (not captopril) - Distribution - pro-drugs converted by liver/small intestine (lisinopril is active) - Excretion by kidneys Therapeutic uses - HTN - Heart failure - MI- reduce mortality and heart failure - Diabetes and nondiabetic nephropathy - Prevention of MI, stroke, and death in patient at high cardiovascular risk Adverse effects - First-dose hypotension - monitor BP for safety - Fetal injury - category D (avoid) - Cough - clears when medication is discontinued - Angioedema - potentially fatal effect - Hyperkalemia -avoid potassium supplements - Dysgeusia and rash - Renal failure - contraindicated with renal artery stenosis  - neutropenia Drug interactions - Diuretics (cuase hypotension) - anti-HTN agents (cause hypotension - Drugs that raise K+ levels ( no supplements) - Lithium (toxicity) - Nonsteroidal anti-inflammatory drugs ( may reduce anit-HTN effects) Prep, dose, admin - Except for enalaprilat, all ACE inhibitors are admin orally - All available in single-drug formulations may be admin without regard to meals Angiotensin II receptor Blockers (ARBs) - Nomenclature - ends with -artan Mechanism of action/pharmacologic effects - Blocks access of angiotensin II to receptos - cause dilation of arterioles and veins - Prevents angiotensin II from inducing pathologic changes ins cardiac sturcutere - Reduces excretion of K+ - Increases renal excretion of Na+ and H2O - Does not inhibit kinase II and increase levels of bradykinin Therapeutic uses - HTN, heart failure, MI - Diabetic-nephropathy - slows progression - If unable to tolerant ACE inhibitors: also provides protection against M”I, STroke, amd death from CV causes in high-risk patients - Migraine headache - May slow the development of diabetic retinopathy Adverse effects - Angioedema - Fetal harm - Renal failure CCB - calcium channel blockers - Drugs that prevent calium ions fro enternoing the cell- mechanism of action - Greatest impact on heart and blood vessles - Used to treat HTN, angina pectoris, and cardiac dysrythmias - Also knowns as calcium antagonist and slow channel blockers Vascular smooth muscle - Calcium channel opens = contractile process - Calcium channel closes = vasdilation Therapeutic doses - Act selectively on peripheral artierol;e and arteries and arterioles of the heart - No significant effect on veins Heart - Myocardium - decreases force of contraction - Sinoatrial (SA) node - decreases (lower HR) - Atrioventricular (AV) node - decreases velocity of conduction across the AV node  - Coupling of cardiac calcium channels to beta1- adrenergic receptors (CCB and beta-blockers have similar effects on the heart) Direct hemodynamic effects - Verapamil and diltiazem act on arterioles and on the heart. There are little or no net effects on cardiac performance with verapamil and diltiazem. The overall effect is vasodilation accompanied by reduced arterial pressure and increased coronary perfusion. Verapamil Therapeutic uses - Angina pectoris- vasospastic angina and angina of effort - Essential HTN - first-line agent - Cardiac dysrhythmias - atrial flutter, atrial fibrillation, paroxysmal supraventricular tachycardia - Migraine AE - Constipation - Most common complaint - Results from blockade of calcium channels in smooth muscle of intestine - Especially severe fro the elderly - Can be decreased by increasing dietary fiber and fluid - Dizziness - Facial flushing - Headache - Edema of ankles and feet - Gingival hyperplasia - Heart blocks Grapefruit juice - Inhibits metabolism and elevates levels of verapamil and can also produce toxicity Drug interactions - Digoxin - risk of AV conduction block and digoxin toxicity - Beta-adrenergic blocking agents - similar effect on the heart; decrease in HR and conductivity Toxicity - Sever hypotension - Bradycardia and AV block - Ventricular tachydysrhythmia - Use gastric lavage and activated charcoal to remove from GI tract; treat above symptoms Important - IV verapamil for dysrhythmias can cause severe cardiovascular effects. Blood pressure and ECG should be monitored with resuscitation equipment immediately available. Diltiazem Actions and uses  - Blocks calcium channels in the heart and blood vessels (similar to verapamil) - Lowers blood pressure—Arteriolar dilation Therapeutic uses - Angina pectoris - Hypertension - Cardiac dysrhythmias—Atrial flutter, atrial fibrillation, paroxysmal tachycardia AE - Similar to verapamil, except for less constipation - Dizziness - Flushing - Headache - Edema of ankles and feet - Exacerbates bradycardia, sick sinus syndrome, heart failure, second- or third-degree heart block Drug interactions - Digoxin - Beta-adrenergic blocking agents Drug-food - Grapefruit juice Beta-adrenergic antagonist (beta-blockers): propranolol and metoprolol - Ends -olol Mechanism of action - Blockade of beta-receptors in the heart, producing - Reduced heart rate - Reduced force of contraction - Reduced velocity of impulse through the AV node Therapeutic applications - Angina pectoris—Reduces oxygen demand - Hypertension—Reduces cardiac output and pulse volume recording (PVR) - Cardiac dysrhythmias—Reduces rate and conductivity - Myocardial infarction—Can reduce mortality and risk - Heart failure—Standard therapy (new)  - Hyperthyroidism—Reduces rapid rhythms - Migraine—May prevent - Stage fright—Prevents tachycardia - Pheochromocytoma—Reduces cardiac stimulation - Glaucoma—Eye drops to reduce intraocular pressure AE - Beta Blockade - Beta 1 Blockade - Beta 2 Blockade Adverse effects of beta blockade: - Adverse effects involve both beta1 and beta2 blockade Adverse effects of beta1 blockade: - Bradycardia - Reduced cardiac output - Precipitation of heart failure - AV heart block - Rebound cardiac excitation—With abrupt withdrawal Adverse effects of beta2 blockade: - Bronchoconstriction - Inhibition of glycogenolysis—Inhibits the breakdown of glycogen to glucose, causing hypoglycemia - Not to be given to diabetics Propranolol - Propranolol is a non-selective beta-blocker. Mechanism - Both beta₁ and beta₂ blockad Therapeutic uses - Hypertension - Angina - Cardiac dysrhythmia - Myocardial infarction AE  - Bradycardia - AV heart block - Heart failure - Rebound cardiac excitation—Do not discontinue abruptly - Bronchoconstriction—May be hazardous for asthmatics and patients with respiratory disorders - Inhibition of glycogenolysis—Can produce hypoglycemia; not for diabetic patients - Central nervous system (CNS) effects—In patients with depression Precautions, warning, contradictions - Severe allergy—Anaphylaxis - Diabetes—Hypoglycemia, and masks hypoglycemic symptoms (tachycardia, etc.) - Cardiac, respiratory, and psychiatric disorders Drug Interactions - Calcium channel blockers—Both work to reduce heart rate and impulse conduction - Insulin—Patients may not recognize a hypoglycemic event Metoprolol - Second generation beta-blocker—Only affects beta₁ receptors, not beta₂ - Mechanism of action—Beta₁ blockade - Therapeutic uses—Hypertension, angina, heart failure, myocardial infarction - Adverse effects of beta₁ blockade - Precautions, warnings, and contraindications - Patients with bradycardia and AV block - Patients with heart failure - Safer for patients with asthma and diabetes (can still mask symptoms of hypoglycemia) Prophylaxis of Coronary Heart Disease (CHD) - Pharmacotherapy focuses on serum cholesterol - Cholesterol and plasma lipoproteins contribute to the development of atherosclerosis - Cholesterol is either exogenous (dietary sources) or endogenous (produced by the liver) - Component of all cell membranes and membranes of intracellular organelles - Required for synthesis of certain hormones and bile salts Role of LDL Cholesterol in Atherosclerosis - LDLs initiate and fuel the development of atherosclerosis  - Process begins with transport of LDLs from the arterial lumen into endothelial cells, then into the space underlying the arterial epithelium - Overall, atherosclerosis is considered an inflammatory process High Cholesterol Cholesterol Screening Recommendations - Every five years for adults older than 20 years - Total cholesterol - HDL cholesterol - LDL cholesterol Treatment of High LDL Cholesterol - Begins with therapeutic lifestyle changes (TLCs) - Smoking cessation - TLC diet - Exercise Drug Therapy for Cholesterol - Drugs should be used only if TLCs fail - Medication options HMG-CoA reductase inhibitors (3-hydroxy-methylglutaryl Coenzyme A) - Bile acid sequestrants - Nicotinic acid (niacin) - Fibrates (reduce levels of TGs, not LDLs) Secondary Treatment Targets - Metabolic syndrome—A group of metabolic abnormalities associated with increased risk of atherosclerotic heart disease and diabetes - Metabolic syndrome is present when three or more of the following are present (or on medications) - High blood glucose—Fasting glucose > 100 mg/dl - High triglycerides— ≥150 mg/dl - Low HDL cholesterol—Below 50 mg/dl for men; 40 mg/dl for women - Hypertension— >130/85 mm Hg - Waist circumference: 40 inches or more for men; 35 inches or more for women - Treatment goals for metabolic syndrome - Reduce the risk for atherosclerotic disease - Reduce the risk for type 2 diabetes - Increase physical activity  - High triglycerides—Levels above 150 mg/dl Drugs and Other Products to Alter Plasma Lipid Levels - High LDL—Most significant contributor to cardiovascular disease - Also consider - High total cholesterol - Low HDL cholesterol - High triglycerides - Drugs can improve lipid profiles, but not all improve clinical outcomes HMG-CoA Reductase Inhibitors (Statins) - Most effective drugs for lowering LDL - Reduction of LDL cholesterol - Elevation of HDL cholesterol - Reduction of triglyceride levels - Nonlipid beneficial cardiovascular actions - Promote plaque stability - Reduce the risk for cardiovascular (CV) events - Increase bone formation Mechanism of Cholesterol Reduction - Increases the number of LD receptors in the liver Therapeutic Uses - Hypercholesterolemia - Primary and secondary prevention of CV events - Post-MI therapy (myocardial infarction) - Diabetes (to reduce mortality from CV disease) Beneficial Actions - Reduction of LDL cholesterol - Elevation of HDL cholesterol - Reduction of triglyceride levels - Nonlipid beneficial cardiovascular actions - Promote plaque stability - Reduce the risk for cardiovascular (CV) events - Increase bone formation Adverse Effects Common - Headache - Rash - GI disturbances - Muscle aches/tenderness in 5–10% of patients Rare - Myositis/Rhabdomyolysis—Tea-colored urine from muscle breakdown - -Hepatotoxicity - New-onset diabetes - Cataracts Drug Interactions - Most other lipid-lowering drugs (except bile acid sequestrants)—May increase severity of adverse events - Drugs that inhibit CYP3A4 increase levels of statins (no grapefruit juice if on a statin) - Use in pregnancy—Category X Dosing - Once-daily in the evening - Endogenous cholesterol synthesis increases during the night - Statins have greatest impact when given in the evening Ezetimibe Mechanism of Action and Impact on Plasma Lipids - Inhibits cholesterol absorption in small intestine Therapeutic Use - Reduces total cholesterol, LDL cholesterol, and apolipoprotein B - Approved for monotherapy and combined use with statins Adverse Effects - Myopathy - Rhabdomyolysis - Hepatitis  - Pancreatitis - Thrombocytopenia Drug Interactions - Statins - Fibrates - Bile acid sequestrants - Cyclosporine Fibric Acid Derivatives (Fibrates) - Most effective drugs available for lowering triglyceride (TG) levels - Can raise HDL cholesterol - Little or no effect on LDL cholesterol - Three drugs in the United States - Gemfibrozil (Lopid) - Fenofibrate (Tricor, others) - Fenofibric acid (TriLipix) Gemfibrozil Effects on Plasma Lipoproteins - Decreases plasma TG content - Lowers VLDL levels - Can raise HDL cholesterol Mechanism - Appears to interact with a specific receptor subtype (PPAR alpha) that increases HDL production Drug Interactions - Statins—Increased risk of myopathy - Displaces warfarin from plasma albumin - Watch for bleeding - Measure international normalized ratio (INR) frequently Therapeutic Uses - Reduces high levels of plasma triglycerides (VLDLs)  - Treatment reserved for patients who have not responded to diet modification - Less effective than statins in reducing LDL - Can raise HDL (not approved for this use) Adverse Effects - Rashes - Gastrointestinal disturbances—Nausea, vomiting, diarrhea - Gallstones - Myopathy - Liver injury (hepatotoxic)—Liver functioning testing at intervals Heart failure ​ Coronary Artery Disease (CAD) CAD—Impaired coronary blood flow, typically atherosclerosis Risks are the same as for atherosclerosis Coronary artery disease has two subgroups ○ Acute coronary syndrome (angina to myocardial infarction) ○ Chronic ischemic heart disease—Recurrent episodes Prevention is important and includes therapeutic lifestyle changes and medications (Statins, etc.) ​ Coronary Atherosclerosis and Vessel Occlusion Atherosclerosis is progressive Two types of atherosclerotic lesions: stable and unstable plaque ○ Stable plaque has a fixed amount of blood flow disruption and produces stable angina ○ Unstable plaque is prone to disruption and therefore unstable angina and myocardial infarction ○ Plaque disruption produces thrombosis and vessel occlusion Thrombosis and vessel occlusion—Results from plaque rupture, expulsion of the lipid core of atherosclerosis, platelet adhesion at the site, and collection of cellular components that occlude the vessel ​ Acute Coronary Syndrome (ACS) ACS is based on the level of atherosclerosis and plaque disruption that results as a spectrum of ischemic responses from angina to myocardial infarction. Ischemia is a reduction in blood flow and may cause angina, heart attack, cardiac dysrhythmias, heart failure, or sudden death. Acute MI causes areas of yellow necrosis Myocardial Infarction (MI)  Infarction—Loss of oxygen to the cardiac tissues as a result of atherosclerosis or abrupt vessel occlusion Manifestations—Pain, severe/crushing, substernal, radiating to left arm, neck, jaw. May have shortness of breath, nausea, vomiting, pale, cool moist skin Diagnosis by clinical presentation, electrocardiogram (EKG) changes, and serum biomarkers (Troponin I, Troponin T, Creatine kinase) Management—Medications, cardiac catheterization, coronary artery bypass grafts ​ Chronic Ischemic Heart Disease Angina Imbalance in blood supply and the heart's oxygen demands Reduction in blood flow from: Atherosclerosis, vasospasm Higher oxygen demand precipitates angina: Stress, exercise, cold Chronic Stable Angina Due to a fixed obstruction Pain when the heart's oxygen demand increases ​ Unstable Angina Due to unstable plaque Pain due to plaque disruptions No evidence of myocardial damage ​ Silent Myocardial Ischemia Myocardial ischemia without pain Autonomic neuropathies, diabetes ​ Variant/Vasospastic Angina (Prinzmetal angina) Pain when coronary arteries spasm ​ Angina pain areas Angina diagnosis and treatment  ○ Diagnostics—EKG, stress test, interventional studies ○ Treatments Non-pharmacologic—Lifestyle, surgical Pharmacologic: Nitrates, beta-blockers, calcium channel blockers ​ Cardiomyopathies Cardiomyopathies are disorders of the heart muscle. Primary—Confined to the myocardium ○ Genetic: Hypertrophic and arrhythmogenic right ventricular ○ Mixed: Dilated and restrictive ○ Acquired: Myocarditis; peripartum and Takotsubo cardiomyopathy Secondary—Part of systemic disorders (multiple organs) that includes the myocardium ​ Hypertrophic Cardiomyopathy Autosomal dominant defects in contractile proteins make cells too weak Cells hypertrophy to do the same amount of work as normal cells Ventricular septum thickens, abnormal diastolic filling Myocardium needs more oxygen and performs less efficiently, so the person is prone to heart failure and may suffer sudden death during exertion Most common cause of sudden death in young athletes Signs/symptoms—Dyspnea, chest pain, exercise intolerance, syncope Diagnosis—Echocardiogram, ECG, continuous cardiac monitoring Treatment—Beta and calcium channel blockers, pacemakers ​ Normal versus Hypertrophic Cardiomyopathy Heart ​ - Normal heart has the aorta, right atrium, left atrium, right ventricle, and left ventricle labeled. Everything is working as it should be. The hypertrophic cardiomyopathy heart has all the same labels with the addition of the pulmonary valve, tricuspid valve, mitral valve labeled. This heart has a smaller  left ventricular cavity due to the thickened left ventricle wall and thickened ventricular septum. Infective Endocarditis Infection of the inner surface of the heart and valves ○ Infective agents (bacteria—staphylococcal)—Introduced through dental procedures, surgery of oral cavity and gut ○ Infection results in progressive enlargement of valvular vegetation ○ Lesions cause valve destruction and systemic effects (emboli, sepsis) At-risk populations—Mitral valve prolapse, congenital heart disease, prosthetic heart valves, implantable devices Acute or sub-acute forms ○ Acute Usually in individuals with normal cardiac valves with IV drug use or debilitated Rapid onset Manifestation—Fever and chills ○ Sub-acute Underlying valve disease developing over several months Manifestations—Persistent bacteremia (may cause microemboli), murmur, low-grade fever, anorexia, malaise, petechiae Treatment—Identify and treat with antibiotics ​ Petechiae 'Death rashes' are more than skin deep Microemboli (splinter hemorrhage) ​ Rheumatic Heart Disease Multisystem inflammatory disease following group A streptococcal (GAS) pharyngitis ○ Inflammation of all layers of the heart  ○ Manifests as acute, recurrent, or chronic Clinical manifestations—Acute form begins after streptococcus A pharyngitis (headache, fever, abdominal pain, nausea, vomiting) Diagnosis—Throat culture, elevated white count, elevated ESR (sedimentation rate), echocardiogram Treatment/prevention—Antibiotics (penicillin), anti-inflammatories, rest ​ Heart Valves Atrial—Ventricular valves (between the chambers of the heart)—Mitral and tricuspid Semilunar valves (between the ventricles and vessels)—Aortic and pulmonic ​ Valve Defects Stenosis The valve will not open all the way It is harder to force blood through it Will hear a murmur from the blood moving through the narrow opening when the valve is open ​ Regurgitation The valve will not close all the way It leaks when "closed" Will hear a murmur from the blood leaking back through the valve that did not close ​ A: Stenosis, B: Regurgitation ​ Identifying Defective Valves Heart murmurs: The blood going through the valve makes a noise Identify heart murmurs by: ○ Where they are (which valve they are near) ○ How they sound (high- or low-pitched) ○ When they happen (systole or diastole) ​ Mitral Valve Disorders Mitral Valve Stenosis Mitral Valve Regurgitation ​ Mitral Valve Stenosis Incomplete opening of the mitral valve Manifestations are dependent on the degree of stenosis—left atrial pressure increase and pulmonary congestion ○ Heart failure presentation with palpitations, chest pain, weakness, fatigue Diagnosis by the presence of a murmur, echocardiogram Treatment—Medication and surgical repair ​ Mitral Valve Regurgitation Incomplete closure of the mitral valve Manifestations—Dependent on the severity of the disease—left ventricular involvement Diagnosis by the presence of a murmur, echocardiogram Treatment—Medication and surgical repair ​ ​ Aortic Valve Disorders Aortic Valve Stenosis Aortic Valve Regurgitation  ​ Aortic Valve Stenosis Increased resistance of blood ejected from the left ventricle to the aorta Causes—Congenital or develops due to calcification Manifestations of heart failure as stenosis become severe Diagnosis—Murmur, angina, syncope, heart failure Treatment—Surgical intervention ​ Aortic Valve Regurgitation Due to an incompetent valve allowing backflow (caused by rheumatic fever, infective endocarditis, congenital defects, hypertension, trauma, etc.) Manifestations—Due to increased left ventricular pressures and backup into the pulmonary system (dyspnea, orthopnea) Diagnosis—Murmur and widened pulse pressure signs Treatment—Aortic valve replacement ​ Heart Failure - Heart failure (HF) is the inability of the heart to function as a pump typified by the inability to maintain cardiac output (CO). It is caused by any disorder that produces reduced pumping ability. This includes CAD, hypertension, cardiomyopathy, and valve disease. Heart failure is classified by the American College of Cardiology/American Heart Association (ACCF/AHA) as Stages A–D and by the New York Heart Association (NYHA) by functional Stages I–IV. Heart Failure Classifications ACCF/AHA Stages NYHA Functional of HF Classifications A At high risk for N HF but without structural heart disease or symptoms of HF B Structural heart I No limitations of physical disease but activity. Ordinary without signs physical activity does or symptoms not cause symptoms of HF of HF. C Structural heart I No limitations of physical disease with activity. Ordinary prior or physical activity does current  symptoms of not cause symptoms HF of HF. II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF. II Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF. I Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest. D Refractory HF I Unable to carry on any requiring physical activity specialized without symptoms of interventions HF, or symptoms of HF at rest. Compensatory Mechanisms in Heart Failure Mechanisms focus on maintaining cardiac output (CO) Decreased cardiac output produces decreased renal blood flow This stimulates the renin-angiotensin-aldosterone system (RAAS) to retain fluid and the sympathetic nervous system to increase heart rate and pulse volume recordings (PVR) to increase cardiac output (CO) The increased pressure in the ventricle results in increased blood backup, myocardium stretch, and oxygen consumption Ultimately, the compensatory mechanisms worsen heart failure ​ Types of Heart Failure Systolic or diastolic failure ○ Normal ejection fraction is 55–70% of blood pumped out of the ventricles with each contraction  ○ Systolic failure—Reduced ejection fraction is < 40% due to decreased myocardial contractility ○ Diastolic failure—Normal ejection fraction but myocardial relaxation is decreased and filling volumes are decreased Right-sided or left-sided failure ○ Right side moves blood into the lungs, but pump failure causes backups into the periphery ○ Left side moves blood into the periphery, but pump failure causes backups into the lungs ​ ​ Right-Sided Heart Failure Diastolic: Right ventricle (RV) does not accept enough blood from body Systolic: RV does not pump enough blood to lungs Effects of impaired pump: Blood backs up (right heart → body → eventually the left heart → lungs); the body fills with fluid—edema observed, lungs do not oxygenate enough blood ​ Left-Sided Heart Failure Diastolic: Left ventricle (LV) does not accept enough blood from lungs Systolic: LV does not pump enough blood to body Effects of impaired pump: Blood backs up (left heart → lungs → eventually the right heart → body); the lungs fill with fluid, body lacks oxygenated blood Pulmonary Edema Due to Heart Failure Capillary fluid moves into alveoli ○ The lungs become stiffer ○ Harder to inhale  ○ Less gas exchange in alveoli ○ Crackles auscultated ○ Frothy pink sputum with severe pulmonary edema Hemoglobin not completely oxygenated and hypoxia results Heart Disease and Children - Congenital defects are attributed to genetic and environmental factors. Proper prenatal care is important to prevent defects that can be attributed to maternal disorders and teratogenic drugs. The clinical manifestations typically are related to shunting of blood, cyanosis, and pulmonary blood flow disruption. Shunting—Diverting blood from atrial to ventricular or from ventricular to atrial circulations Cyanotic vs. acyanotic—Does the blood become deoxygenated? Pulmonary blood flow—Does the defect cause a decrease or increase in pulmonary blood flow? ​ Shunts Fetal circulation: Ductus venosus, Ductus arteriosus, ​ - Fetal circulation is an internal drawing with the following features labeled: superior vena cava, ductus venosus, umbilical vein, umbilical arteries, aortic arch, ductus arteriosus, inferior vena cava, and descending aorta. An opening or connection that lets blood move from one side of the circulation to the other Most occur in the heart and move blood either from left to right or from right to left ○ Because the left side is stronger, blood is usually pushed from the left to right side (termed a left-to-right shunt) Shunts are part of fetal circulation and are normal before birth  Ductus venosus—Lets blood flow from the visceral veins to the vena cava, bypassing the liver Foramen ovale—Lets blood flow from the right atrium to the left atrium to bypass the lungs Ductus arteriosus—Lets blood flow from the pulmonary trunk to the aorta to bypass the lungs ​ Foramen ovale, ​ - Left-to-right shunts ○ Less blood to the body ○ More blood to the lungs Right-to-left shunts ○ Deoxygenated blood to the body ○ Less blood to the lungs ​ Congenital Heart Defects Patent ductus arteriosus—The ductus closes in a majority of infants within 48 hours Size of the ductus determines manifestations—Blood moves from higher to lower pressures (typically left to right) Manifestations—Murmur If untreated, long-term consequences Diagnosis—Echocardiogram Treatment—NSAIDs, surgery ​ Septal Defects Persistent openings between heart chambers ○ Atrial septal defects—Can be asymptomatic, but typically there is shunting of blood to the pulmonary system and a risk of pulmonary vascular disease after 20 ○ Ventricular septal defects—Size of defect determines manifestations Manifestations of the left-to-right shunt (tachypnea, diaphoresis during feeding) Diagnosis—Echocardiogram Treatment dependent on size of defect—Follow if small, interventional procedures if larger  ​ Tetralogy of Fallot 5–7% of cyanotic congenital defects Consists of four defects ○ Ventricular septal defect ○ Shifting of the aorta to the right ○ Narrowed pulmonary outflow ○ Right ventricular hypertrophy Cyanosis present due to blood flow restriction to the lungs Hyper-cyanosis during crying and feeding Surgical revision required Transposition of the Great Arteries  Aorta arises from the right ventricle Pulmonary artery from the left ventricle Requires shunting for survival Shunting can be from ○ Patent ductus arteriosus ○ Septal defect Manifestations of cyanosis Surgery required to realign arteries ​.Coarctation of the Aorta Localized narrowing of the aorta Manifestations—Pulses and blood pressure differ ○ Bounding pulses and high pressure in arms and carotid pulses ○ Weak pulses and pressures in the femoral, popliteal, and dorsalis pulses Diagnosis—Blood pressure If modest and untreated, leads to LV hypertrophy Severe cases cause heart failure in infants Treatment—Surgery Functional Single-Ventricle Anatomy Hypo-plastic left heart syndrome Pulmonary and systemic circulation is mixed Manifestations—Cyanosis Surgical repair to redirect systemic circulation to the pulmonary system and use the single ventricle to move oxygenated blood to systemic circulation Heart transplant is an option ​ Pharmacology for Heart Failure Pharmacology for Atherosclerosis Refer to the medication sheets developed for Module 5. There is no additional information in this Module. Pharmacology for Heart Failure The basis of heart failure therapy consists of three types of medications: ○ Diuretics—To reduce vascular volume (this content will be covered in the renal module) ○ Inhibitors of the RAAS—To reduce the dilation of the vascular bed ○ Beta-blockers—Three specific agents to improve LV ejection fraction and exercise tolerance These are carefully monitored Additional agents include digoxin Angiotensin-Converting Enzyme Inhibitors (ACEs) See the previously developed medication sheet  ACE inhibitors are used to improve functional status and prolong life expectancy Mechanism of action and overview of pharmacologic effects ○ Reducing levels of angiotensin II ○ Increasing levels of bradykinin Heart failure effects: ○ Hemodynamic benefits—Reducing levels of angiotensin II dilates arterioles and improves sodium and water excretion ○ Cardiac remodeling—The increase in bradykinin supports a favorable effect on cardiac remodeling Therapeutic Uses Hypertension Heart failure Myocardial infarction (MI)—Reduce mortality and heart failure Diabetic and nondiabetic nephropathy Prevention of MI, stroke, and death in patients at high cardiovascular risk ​ Adverse Effects First-dose hypotension Fetal injury Cough Angioedema Hyperkalemia Dysgeusia and rash Renal failure with renal artery stenosis Neutropenia ​ Drug Interactions Diuretics (hypotension) Antihypertensive agents Drugs that raise potassium levels (no supplements) Lithium (toxicity) Nonsteroidal anti-inflammatory drugs (may reduce antihypertensive effects) ​ Angiotensin-II Receptor Blockers (ARBs) Mechanism of action and overview of pharmacologic effects for heart failure ○ Block access of angiotensin II ○ Cause dilation of arterioles and veins ○ Prevent angiotensin II from inducing pathologic changes in cardiac structure ○ Reduce excretion of potassium ○ Decrease release of aldosterone ○ Increase renal excretion of sodium and water  ○ Do not inhibit kinase II and levels of bradykinin—Therefore, no positive effects on cardiac remodeling ​ Therapeutic Uses Hypertension, heart failure, myocardial infarction Diabetic nephropathy If unable to tolerate ACE inhibitors: protection against MI, stroke, and death from cardiovascular (CV) causes in high-risk patients Migraine headache May prevent development of diabetic retinopathy ​ Adverse Effects Angioedema Fetal harm Renal failure ​ Due to the lack of effect on kinin levels (cardiac remodeling), ACE inhibitors are the preferred heart failure therapy. ARBs are prescribed to patients unable to tolerate ACE inhibitors. Digoxin (Cardiac Glycoside) Mechanical and electrical effects Positive inotropic actions ○ Increase myocardial contractile force ○ Alter electrical activity of the heart ○ Favorably affect neurohormonal systems Relationship of potassium to inotropic action ○ Potassium levels must be kept in normal physiologic range (3.5–5.0) ​ Hemodynamic Benefits Increased cardiac output ○ Decreased sympathetic tone ○ Increased urine production ○ Decreased renin release ​ Neurohormonal Benefits Modulates the activity of the neurohormonal system ○ Suppresses renin release in the kidney ○ Decreases sympathetic outflow from the CNS ○ Increases sensitivity of cardiac baroreceptors ​ Electrical Effects  Alters electrical properties of the heart ○ Increases firing rate of vagal fibers Check the pulse before administering—digoxin can decrease pulse rate ○ Increases responsiveness of sinoatrial (SA) node to acetylcholine ​ Adverse Effects Cardiac dysrhythmias Predisposing factors to dysrhythmia ○ Hypokalemia (monitor potassium) ○ Elevated digoxin level—Narrow therapeutic range (0.5–0.8 ng/mL) ○ Heart disease Diagnosing digoxin-induced dysrhythmias is difficult since dysrhythmia may be due to underlying cardiac disease Managing digoxin-induced dysrhythmias ○ Monitor digoxin and potassium levels ○ May have an antidysrhythmic prescribed Measures to reduce adverse effects ​ Non-Cardiac Adverse Effects Anorexia Nausea Vomiting Fatigue Blurry vision Patient Education Education should focus on interventions to reduce toxicity and careful management if the patient is also taking potassium ​ Drug Interactions Diuretics—May decrease potassium levels ACE inhibitors and ARBs—May increase potassium levels Sympathomimetics—Produce tachydysrhythmias Quinidine—Elevates levels of digoxin Verapamil—Elevates levels of digoxin Dysrhthmias ​ Electrical Properties of the Heart Cardiac Conduction - Cardiac conduction diagram. Heart labeled with SA node, AV node, bundle of His, left posterior fascicle, left anterior fascicle, Purkinje fibers, right bundle branch, and left bundle branch. There is then a line that curves up steeply and down in a slope labeled A and pointing to the SA node and AV node. ​ - Line B goes straight up to a sharp corner before sloping downward and is pointing at the connecting lines between SA node and AV node. Line C also goes straight up to a sharp curve but decreases slower at first before dropping into a more drastic downward slope and is pointing to the Purkinje fibers and outer area of the heart. Impulse conduction: ○ Sinoatrial (SA) node—Pacemaker of the heart ○ Atrioventricular (AV) node—Between the atria and ventricles ○ His-Purkinje system—Distributes the electrical impulse through the ventricles Normal conduction: ○ Specialized cardiac cells that can generate an impulse are present in the sinoatrial (SA) node and the atrioventricular node (AV) ○ Cardiac muscle conducts the electrical activity generated in a typical pattern that produces cardiac output ○ Cardiac muscle depolarizes and repolarizes to generate an action potential ○ Ions (sodium, potassium, calcium) are critical to the development of an action potential ○ Electrocardiogram (ECG) Provides a graphic representation of cardiac electrical activity Major components of an ECG ○ P wave: Depolarization in the atria ○ QRS complex: Depolarization of the ventricles ○ T wave: Repolarization of the ventricles ​ Dysrhythmia An abnormality in the rhythm of the heartbeat (also known as arrhythmia) Arises from impulse formation disturbances Dysrhythmias result from congenital defects, degeneration over time, damage to the myocardium, electrolyte imbalances Virtually all drugs that treat dysrhythmias can also cause dysrhythmias Dysrhythmias of Atrial Rhythm—Supraventricular Rhythmic disturbances that originate above the ventricles in the atria, the SA node, or AV node Rhythm may be ○ Regular or irregular ○ Normal rate (60–100), tachycardic (above 100), or bradycardia (rate below 60) ○ Symptomatic or asymptomatic Not typically life-threatening, but produce reduced cardiac output ​ Supraventricular Rhythm—Atrial Fibrillation Loss of coordinated electrical activity in the atria ○ No P wave on EKG tracing Impairs ventricular filling and therefore cardiac output  Symptoms are minimal to severe Due to incomplete atrial emptying—Blood pooling in the atria and high risk for formation of thrombi Treatment ○ Anticoagulants required for patients in chronic atrial fibrillation ○ Antidysrhythmics ​ Ventricular Dysrhythmias Originate in the ventricles or Bundle of His Typically symptomatic—Loss of consciousness or death Immediate intervention required Causes: MI, cardiomyopathies, electrolyte disorders, hypoxia, valvular disorders, drug toxicity ​ Premature ventricular contractions, Source: quizlet.com Ventricular tachycardia ​ Antidysrhythmic Drugs Generation of dysrhythmias—Two types Disturbance of impulse formation Disturbance of impulse conduction ​ Classification of Antidysrhythmic Drugs Vaughan Williams classification Class I: Sodium channel blockers Class II: Beta-blockers Class III: Potassium channel blockers Class IV: Calcium channel blockers Other: Adenosine, digoxin, and ibutilide (will not be discussed here) ​ Prodysrhythmic Effects of Antidysrhythmic Drugs Antidysrhythmic drugs should be used only when dysrhythmias are symptomatically significant, and only when the potential benefits clearly outweigh the risks. All antidysrhythmic drugs can produce or worsen dysrhythmias. Principles of Antidysrhythmic Drug Therapy Balancing Risks and Benefits Consider properties of dysrhythmias ○ Sustained versus nonsustained—Typically treated symptomatically ○ Asymptomatic versus symptomatic ○ Supraventricular versus ventricular—Supraventricular are typically benign, but treatment is needed for rhythms that interfere with ventricular filling and output ​ Acute and Long-Term Treatment Phases Treat to terminate an acute problem Long-term therapy is aimed at prevention of reoccurrence ​ Minimizing Risk Start with low dose Monitor drug level Monitor effect (Holter monitor) ​ Class I: Sodium Channel Blockers Lidocaine Lidocaine is only for ventricular dysrhythmias and only administered by IV. Lidocaine is also a local anesthetic. Mechanism of action—Effects on the heart ○ Blocks cardiac sodium channels—Slows conduction in the atria, ventricles, and His-Purkinje system ○ Reduces automaticity in the ventricles and His-Purkinje system ○ Accelerates repolarization Adverse effects  ○ CNS effects—Drowsiness, confusion, paresthesias with high doses ○ Toxic doses—Seizures, respiratory arrest ​ Class II: Beta-Blockers Beta-adrenergic blocking agents—Only four approved for treating dysrhythmias Propranolol Propranolol is a nonselective beta-adrenergic antagonist. Mechanism of action—Effects on the heart and ECG ○ Decreased automaticity of the SA node ○ Decreased velocity of conduction through the AV node ○ Decreased myocardial contractility Therapeutic use ○ Dysrhythmias caused by excessive sympathetic stimulation ○ Supraventricular tachydysrhythmias Suppression of excessive discharge Slowing of ventricular rate Adverse effects ○ Heart block—Patients should be taught to check their pulse before taking the medication ○ Heart failure ○ AV block ○ Sinus arrest ○ Hypotension ○ Bronchospasm (in asthma patients) ​ Class III: Potassium Channel Blockers Amiodarone Therapeutic use ○ For life-threatening ventricular dysrhythmias only ○ Recurrent ventricular fibrillation ○ Recurrent hemodynamically unstable ventricular tachycardia Effects on the heart and ECG ○ Reduced automaticity in the SA node ○ Reduced contractility ○ Reduced conduction velocity ○ QRS widening ○ Prolongation of the PR and QT intervals ​ - Amiodarone: Keratopathy, Whirl-like opacities in the corneal epithelium. They appear in nearly 100%  of patients treated for more than six months with amiodarone. Source: Kellogg.umich.edu Amiodarone has serious toxicities that may persist for months. Adverse effects ○ Protracted half-life ○ Pulmonary toxicity—Pneumonitis, fibrosis. 10% mortality ○ Cardiotoxicity—Can precipitate heart failure ○ Liver—Monitor periodically for liver failure ○ Toxicity in pregnancy and breastfeeding ○ Corneal microdeposits—Almost all patients develop microdeposits that do not affect sight ○ Optic neuropathy—Rare Drug and food interactions ○ Amiodarone levels can be increased by grapefruit juice and by inhibitors of CYP3A4 Toxicity can result ○ Amiodarone levels can be reduced by cholestyramine (which decreases amiodarone absorption) and by agents that induce CYP3A4 (for example, St. John’s wort, rifampin) ○ The risk of severe dysrhythmias is increased by diuretics (because they can reduce levels of potassium and magnesium) and by drugs that prolong the QT interval, of which there are many ○ Combining amiodarone with a beta-blocker, verapamil, or diltiazem can lead to excessive slowing of the heart rate ​ Class IV: Calcium Channel Blockers Verapamil and Diltiazem Effects on the heart ○ Reduce SA nodal automaticity ○ Delay AV nodal conduction ○ Reduce myocardial contractility Therapeutic uses ○ Slow ventricular rate (atrial fibrillation or atrial flutter) ○ Terminate supraventricular tachycardia (SVT) caused by an AV nodal reentrant circuit Adverse effects ○ Bradycardia ○ Hypotension ○ AV block ○ Heart failure ○ Peripheral edema ○ Constipation Drug interactions ○ Can elevate digoxin levels ○ Increased risk of bradycardia when combined with a beta-blocker ​ Drugs for Angina Pectoris Overview  Angina pectoris is a sudden pain beneath the sternum, often radiating to the left shoulder and arm. The oxygen supply to the heart is insufficient to meet the oxygen demand. There are two goals of angina drug therapy: Prevention of myocardial infarction and death Prevention of myocardial ischemia and anginal pain ​ Determinants of Cardiac Oxygen Demand and Supply Heart rate Myocardial contractility Intramyocardial wall tension (preload/afterload) ​ Oxygen Supply Myocardial blood flow Myocardial perfusion occurs only in diastole ​ Drugs for Angina Pectoris There are three families of antianginal agents: Organic nitrates—Nitroglycerin Calcium channel blockers—Example: Verapamil Beta-blockers—Example: Metoprolol ​ Organic Nitrates Nitroglycerin Used for stable and variant angina Vasodilator (dilates veins) Acts directly on vascular smooth muscle (VSM) to promote vasodilation Mechanism of action—Decreases cardiac oxygen demand by conversion of nitrate to nitric oxide Adverse effects ○ Headache ○ Orthostatic hypotension ○ Reflex tachycardia ​ Sublingual medicine: Glyceryl trinitrate (GTN) is often given for angina/chest pain via the sublingual route, under the tongue where there are lots of blood vessels so that the pain can be relieved quickly, Source: St. Monica Trust provided by rxlist.com Drug interactions ○ Hypotensive drugs—Intensify effects of hypotension ○ Phosphodiesterase type 5 inhibitors (example Viagra)—Can precipitate dangerous drops in blood pressure ○ Beta-blockers, verapamil, and diltiazem Routes of administration ○ Sublingual tables—Rapid results ○ Sustained-release capsules—Sustained effects ○ Transdermal delivery—Daily application Therapeutic uses ○ Acute anginal therapy ○ Sustained anginal therapy ○ IV for perioperative control of blood pressure and treatment of heart failure with myocardial infarction (MI), unstable angina, and uncontrolled exacerbations of chronic angina Tolerance ○ Can develop rapidly ○ Cross-tolerance to all other nitrates ○ To minimize, use the lowest effective dose ○ For long-acting formulas (extended-release or transdermal): eight drug-free hours per day Calcium Channel Blockers Verapamil Blocks calcium channels in vascular smooth muscle Used for stable and variant angina (can relax coronary artery spasm) Adverse effects ○ Dilation of peripheral arterioles ○ Reflex tachycardia ○ Hypotension ○ Beta-blockers ○ Bradycardia ○ Heart failure  ○ AV block ​ Beta-Blockers Beta-blockers decrease cardiac oxygen demand—Effective for exertional angina Propranolol, metoprolol (not effective for vasospastic angina) Adverse effects ○ Bradycardia ○ Decreased atrioventricular (AV) conduction ○ Reduction of contractility ○ Asthmatic effects (propranolol) ○ Use with caution in patients with diabetes ○ Insomnia ○ Depression ○ Bizarre dreams ○ Sexual dysfunction ​ Reduction of Angina Risk Factors Nondrug therapy ○ Avoid factors that can precipitate angina ○ Decrease risk factors Risk factors ○ Smoking ○ High cholesterol ○ Hypertension ○ Diabetes ○ Physical inactivity ​ Anticoagulants Physiology and Pathophysiology of Coagulation Physiology—Hemostasis Pathophysiology—Thrombosis ​ Physiology—Hemostasis Stage I: Formation of platelet plug ○ Platelet aggregation Stage II: Coagulation ○ Intrinsic coagulation pathway ○ Extrinsic coagulation pathway Keeping hemostasis under control Physiologic removal of clots ​ Pathophysiology—Thrombosis Atrial thrombosis Venous thrombosis ​ Drugs for Thromboembolic Disorders Three major groups: Anticoagulants: Disrupt the coagulation cascade, thereby suppressing the production of fibrin Thrombolytics: Promote lysis of fibrin, causing dissolution of thrombi Antiplatelets: Inhibit platelet aggregation ​ Anticoagulants Reduce the formation of fibrin Two mechanisms of action ○ Inhibit the synthesis of clotting factors (Warfarin) ○ Inhibit the activity of clotting factors ​ Heparin (unfractionated) Mechanism of action—Enhances antithrombin activity which inactivates the clotting factors thrombin and factor Xa Rapid-acting anticoagulant Administered by injection only (prescribed in units) ○ Intravenous administration—Continuous and intermittent ○ Deep subcutaneous (subQ)—Given minimally two inches away from umbilicus in abdomen Therapeutic uses ○ Preferred anticoagulant during pregnancy and when rapid anticoagulation is required ○ Pulmonary embolism (PE) ○ Stroke evolving ○ Massive deep vein thrombosis (DVT)  ○ Open heart surgery ○ Renal dialysis ○ Low-dose therapy postoperatively ○ Disseminated intravascular coagulation (DIC) ○ Adjunct to thrombolytic therapy Adverse effects ○ Hemorrhage (10% of patients)—Primary adverse effect, may be fatal ○ Heparin-induced thrombocytopenia (HIT)—Immune response with decreased platelet counts and increased thrombosis ○ Hypersensitivity reactions—Sources of heparin are animal tissues Contraindicated—Any patient with a high likelihood of bleeding ○ Thrombocytopenia ○ Uncontrollable bleeding ○ During and immediately after surgery of the eye, brain, or spinal cord Antidote for overdose (OD): Protamine sulfate Laboratory monitoring required—Activated partial thromboplastin time (aPTT) ​ Important Heparin is a high-alert medication with various concentrations. Low-Molecular-Weight (LMW) Heparin Enoxaparin Enoxaparin Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin Mechanism of action is the same as heparin Therapeutic uses ○ Prevention of deep vein thrombosis (DVT) after surgery (including replacement of hip, knee) ○ Treatment of established DVT ○ Prevention of ischemic complications (patients with unstable angina and some myocardial infarctions) Administered subQ Dosage based on body weight Antidote for toxicity: Protamine sulfate Costs more than unfractionated heparin Does not require monitoring; therefore can be given at home Adverse effects and interactions ○ Bleeding (but less than with unfractionated heparin) ○ Immune-mediated thrombocytopenia  ○ Severe neurologic injury for patients undergoing spinal puncture or spinal-epidural anesthesia Administration ○ Subcutaneous of the abdomen, avoiding the umbilicus ○ Is available in pre-filled syringe ​ Warfarin An oral vitamin K antagonist Used as rat poison Mechanism of action ○ Blocks biosynthesis of factors VII, IX, and X and prothrombin ○ Does not affect factors that are already present ○ This produces a delayed effect—May take several days to develop Therapeutic uses ○ Not useful in emergencies due to delayed effect ○ 99% of warfarin is bound to albumin Unbound warfarin moves across membranes easily (placenta and milk-producing glands) ○ Long-term prophylaxis of thrombosis Prevention of venous thrombosis and associated pulmonary embolism Prevention of thromboembolism (in patients with prosthetic heart valves) Prevention of thrombosis during atrial fibrillation Monitoring treatment ○ Prothrombin time (PT) ○ International normalized ratio (INR) (therapeutic levels are reached when the INR is two to three times normal) Adverse effects Hemorrhage ○ Antidote—vitamin K Fetal hemorrhage and teratogenesis from use during pregnancy Avoid use during lactation (warfarin enters breast milk) Drug interactions ○ Drugs that increase anticoagulant effects ○ Drugs that promote bleeding ○ Drugs that decrease anticoagulant effects ○ Heparin ○ Aspirin ○ Acetaminophen Food and vitamin K ○ Foods with vitamin K should not be changed radically in the diet (mayonnaise, canola and soybean oil, green leafy vegetables) ​ Direct Oral Anticoagulants Direct Thrombin Inhibitors Mechanism of action—Direct inhibition of thrombin (unlike heparin, which enhances the activity of  antithrombin) Dabigatran etexilate Oral prodrug that undergoes conversion to dabigatran Advantages ○ Does not require monitoring of anticoagulation ○ Little risk of adverse interactions ○ Same dose can be used for all patients regardless of weight or age Therapeutic uses ○ Atrial fibrillation (non-valvular) ○ VTE prevention after knee or hip replacement ○ DVT/PE prevention Adverse effects ○ Bleeding—No specific antidote to reverse dabigatran-related bleeding ○ Gastrointestinal (GI) disturbances—35% of patients experience dyspepsia- and gastritis-like symptoms ​ Antiplatelets Antiplatelet Drugs Aspirin (ASA) Mechanism of action ○ Suppresses platelet aggregation through irreversible inhibition of cyclooxygenase ○ Effects persist between seven to ten days Therapeutic uses ○ Prevention of ischemic stroke and transient ischemic attack (TIA) ○ Stable and unstable angina ○ Prevention of coronary stent re-occlusion ○ Primary prevention of MI (81 mg to 325 mg per day) ○ Acute MI Adverse effects ○ Bleeding ○ GI bleeding and hemorrhage stroke ○ Enteric-coated tablets may not reduce the risk of GI bleeding ○ Salicylism – causes tinnitus (withhold aspirin) Endocrine Endocrine Overview - The endocrine system is specialized tissues that produce chemical messengers (hormones) that mediate growth and function within the body. It uses the vascular system to deliver messengers to target organs. An altered function is due to hypofunction, hyperfunction, or resistance of the target cells. Examples: pituitary gland, thyroid, adrenals, pancreas, gonads Pancreas Function Overview Pancreas cells labeled with pancreatic acini, alpha cell, beta cell, delta cell, islet of Langerhans, and red blood cells. Exocrine acini → digestive enzymes → duct → duodenum Endocrine islets of Langerhans → hormones → blood → target tissues/organ ○ Beta cells → Insulin, amylin ○ Alpha cells → Glucagon ○ Delta cells → Somatostatin ○ F/PP cells → Pancreatic polypeptide ​ Glucose Regulation Insulin Hormonal control of glucose metabolism is from the endocrine pancreas ○ Produced by the beta cells in the islet of Langerhans of the pancreas after a rise in blood sugar is detected ○ The only hormone that lowers blood glucose levels ○ Binds to the target cell surface and activates the process for glucose to enter the cell ○ Excess glucose is stored in the liver as glycogen, which is stored and released by the liver to maintain blood glucose levels ​ Beta Cells and Insulin Increased blood glucose triggers insulin secretion (the only hormone that decreases blood sugar) Insulin stimulates the uptake, use, and storage of glucose ○ 2/3 of glucose converted to glycogen (glycogenesis) and stored in the liver ○ Excess glucose converted to fat (lipogenesis) As glucose levels decrease, glycogen is converted to glucose (glycogenolysis) and released into the blood Note—The brain only uses glucose for energy ​ Insulin Actions Promoting uptake of glucose by target cells Inhibiting fat and glycogen breakdown ○ Glycogen breakdown is termed glycogenolysis  Inhibits protein breakdown and increases protein synthesis ○ If not enough glucose or insulin is available, the body breaks down protein into glucose (gluconeogenesis) ​ Glucagon Glucagon is a hormone that maintains blood glucose between meals. Decreased blood glucose causes glucagon secretion by the pancreatic alpha cells ○ High blood amino acids also stimulate secretion Glucagon stimulates the release of glucose into the blood ○ Glycogen converted to glucose (glycogenolysis) ○ Fat → fatty acids for energy (lipolysis) ○ Amino acids → glucose (gluconeogenesis) ​ Diabetes Mellitus Abnormal carbohydrate, protein, and fat metabolism Significant risk factor for coronary heart disease and stroke The leading cause of blindness, chronic kidney disease, and amputation Identified through laboratory tests and clinical manifestations ​ Diagnosis and Management Laboratory Testing Blood Glucose Testing Random ≥ 200 mg/dL and symptoms Fasting > 126 mg/dL ​ Oral Glucose Tolerance Test Value of ≥ 200 mg/dL at two hours Hemoglobin A1C > 6.5% Goal for the management of diabetes is 6.5–8.0% Types of Diabetes Mellitus Prediabetes Type I (A and B) Type II Gestational diabetes mellitus Other specific types of diabetes ○ Genetic defects in beta-cell function ○ Diabetes secondary to other diseases, drugs, or transplant ​ Prediabetes Identified by:  ○ Impaired fasting plasma glucose between 100 mg/dL and 125 mg/dL ○ Impaired glucose tolerance test Increased risk for developing Type II diabetes May reduce risk with diet changes and exercise and possibly with certain oral antidiabetic drugs Many people who meet the criteria for “prediabetes” never develop diabetes, even if they do not take precautions against diabetes ​ Type I Diabetes Mellitus Type I diabetes mellitus—5–10% of diabetics ○ Type IA is typified by immune-mediated destruction of pancreatic beta cells; antibodies can be detected ○ Type IB is termed idiopathic since no antibodies are found More commonly found in younger individuals Characterized by absolute lack of insulin with elevated blood glucose and breakdown of fats and proteins (prone to ketoacidosis) Absolute lack of insulin requires insulin replacement Clinical manifestations specific to Type I ○ Sudden onset ○ Weight loss Treatment—Insulin replacement, self-monitoring blood sugars, dietary and lifestyle changes ​ Type II Diabetes Type II—90–95% of diabetes cases Typified by relative insulin deficiency beta-cell dysfunction, insulin resistance, and increased glucose production by the liver Strong genetic component More common in adults who are overweight, but an alarming number of children and adolescents are developing Type II diabetes ​ Pathogenesis of Type II Diabetes - Pathogenesis of Type 2 Diabetes diagram. Starting with either genetic predisposition or environmental factors and ending with type 2 diabetes. From genetic predisposition, the pathway can go to the pancreas, there can be deranged insulin release to tissues, especially muscle, liver, and fat,  decreased glucose uptake, hyperglycemia, and resulting in type 2 diabetes. From the pancreas, it could also go to the liver where there is increased hepatic glucose output, to hyperglycemia, and resulting in type 2 diabetes. From genetic predisposition to insulin resistance, it goes to the tissues, especially muscle, liver, and fat, decreased glucose uptake, hyperglycemia, and resulting in type 2 diabetes. From genetic predisposition or environmental factors, it goes to obesity, to insulin resistance, to the tissues, especially muscle, liver, and fat, decreased glucose uptake, hyperglycemia, and resulting in type 2 diabetes. Relative insulin deficiency—Beta cells are able to produce insulin Insulin resistance—Decreased ability of insulin to act on target tissue (muscle, liver, fat) ○ Associated with obesity and physical inactivity Type II diabetes mellitus (DM) is more common than Type I DM. True Gestational Diabetes Pregnant woman becomes intolerant to insulin (second and third trimester) Women with gestational diabetes are more susceptible to complications of pregnancy, mortality, and fetal abnormalities Typically resolves once the baby is delivered 20–50% chance of developing diabetes in the next ten years ​ Clinical Manifestations of Diabetes Due to hyperglycemia and glucosuria ○ Polyuria (and glycosuria)—Excessive urination ○ Polydipsia—Excessive thirst ○ Polyphagia (not in Type II)—Excessive hunger Other (due to hyperglycemia): blurry vision, fatigue, skin infections; Type I: weight loss ​ Metabolic Syndrome (Insulin Resistance Syndrome) Apple- and pear-shape obesity Linked to Type II diabetes and other metabolic abnormalities Major factor is obesity Components are: ○ Hyperglycemia ○ Intra-abdominal obesity (upper body or ‘apple’ shape) ○ Increased blood triglyceride levels ○ Decreased HDL levels ○ Increased blood pressure ○ Systemic inflammation ​ Obesity Patterns Apple shape: Metabolic and cardiovascular risks  Pear shape: Mechanical (knee damage) and varicose vein risk ​ Complications of Diabetes Mellitus Acute Complications Counter-regulatory mechanisms—Produced by other hormones involved in glucose regulation (catecholamines, glycogen, cortisol) ○ Somogyi effect—Hypoglycemic episodes after hyperglycemia ○ Dawn phenomenon—Increased insulin need in the mornings due to circadian variations in hormone secretions ​ Diabetic Ketoacidosis (DKA) More likely in Type I, but also Type II with stress ○ Ranges from mild to severe (life-threatening) Lack of insulin and decrease in glucose utilization produces hyperglycemia, ketosis, metabolic acidosis ○ Causes dehydration, loss of electrolytes Clinical manifestations—‘Fruity’ odor to breath, hypotension, tachycardia, Kussmal (rapid and deep) respirations, lethargy to stupor Treatment—Insulin, fluid, and electrolyte replacement ​ Hyperglycemic Hyperosmolar State More likely in Type II diabetics—Decreased glucose utilization leads to hyperglycemia and dehydration, polyuria, no ketosis Blood glucose is > 600 mg/dL Clinical manifestations—CNS symptoms, weakness, dehydration, polyuria, neurologic alterations (hemiparesis, aphasia, seizures, coma—can be mistaken for stroke) Treatment—Treat hyperglycemia; careful fluid and electrolyte replacement and monitor for cerebral edema Hypoglycemia Blood sugar levels of < 70mg/dL ‘Insulin reaction’ producing low blood sugar (too much insulin or hypoglycemic medications, exercise, not eating) Rapid onset and progression—Variable clinical manifestations ○ Autonomic reactions—Sweating, cool and clammy skin, tachycardia ○ CNS reactions—Headache, altered behavior Treatment—Give oral glucose or, if unable to swallow, IM or subQ glucagon ​ Chronic Complications Chronic complications of diabetes mellitus ​ - Chronic complications of diabetes mellitus diagram. Human body labeled with the following information. Autonomic neuropathy includes dizziness and syncope. Eye includes retinopathy, cataracts, glaucoma. Microangiopathy includes cerebral infarcts, hemorrhage. Atherosclerosis in the heart includes ischemic heart disease, myocardial infarct. Disorders of gastrointestinal motility include delayed gastric, emptying, diarrhea, constipation. Genitourinary tract includes bladder stasis and infection, erectile dysfunction in males. Nephropathy includes glomerulosclerosis, chronic kidney disease. Atherosclerosis in the lower legs include peripheral vascular disease, gangrene, infections. Somatic neuropathy includes abnormal sensory and motor function, foot ulcers. Majority of complications are related to the level of chronic hyperglycemia Complications include: ○ Microvascular ○ Macrovascular ○ Foot ulcers/infection  Prevention of chronic complications—Tight control of blood glucose, normal lipid levels, control of hypertension ​ Microvascular—Diabetic Neuropathies Somatic neuropathy—Peripheral neuropathy ○ Diminished perception: Vibration, pain, temperature ○ Hypersensitivity: Light touch, occasionally severe “burning” pain Autonomic neuropathy ○ Defects in vasomotor and cardiac responses ○ Inability to empty the bladder ○ Impaired motility of the gastrointestinal tract ○ Sexual dysfunction Leading cause of renal disease Risk factors—Predisposition, hypertension, smoking, poor glycemic control, hyperlipidemia Glomerular effects due to basement membrane damage of the blood vessels causing increased urine albumin Prevention—Glycemic control, hypertension control, treat hyperlipidemia, smoking cessation ​ Microvascular - Diabetic Nephropathy Leading cause of renal disease Risk factors - predisposition, hypertension, smoking, poor glycemic control, hyperlipidemia Glomerular effects due to basement membrane damage of the blood vessels - increased urine albumin prevention - glycemic control, hypertension control, treat hyperlipidemia, smoking cessation ​ Diabetic retinopathy ​ - Diabetic retinopathy diagram labeled with hemorrhages, abnormal growth of blood vessels, aneurysm, "cotton wool" spots, and hard exudates Microvascular—Retinopathy Leading cause of blindness is diabetes Retinal abnormalities can result in hemorrhage and abnormal blood vessel growth Risk factors and prevention—Hypertension, smoking, poor glycemic control, hyperlipidemia  Annual eye examinations are recommended ​ Macrovascular Complications Coronary artery disease, cerebrovascular disease, peripheral vascular disease Risk factors—Obesity, hypertension, hyperglycemia, hyperinsulinemia, systemic inflammation Aggressive management of cardiovascular risk factors—Metabolic syndrome ​ Foot ulcers ​ Foot Ulcers Most common complication leading to hospitalization Due to neuropathy (lack of sensation to injury) and vascular insufficiency ​ Infections Infections occur at a higher rate in diabetic patients—Soft tissue, osteomyelitis, urinary tract, pyelonephritis, and candida Due to impaired circulation (macro and micro), hyperglycemia, sensory deficits Pharmacology for Diabetes Primary goal is to prevent long-term complications Tight control of blood glucose level is important Controlling blood pressure and blood lipids also is important to prevent chronic complications ​ Type I Diabetes Physical activity—150 minutes per week Insulin replacement Management of hypertension An ACE inhibitor (for example, lisinopril) or an ARB (for example, losartan) can reduce the risk of diabetic nephropathy Dyslipidemia  Statins (for example, atorvastatin) Requires a comprehensive plan ○ Integrated program of diet, self-monitoring of blood glucose, exercise, and insulin replacement ​ Dietary Measures Evidence suggests no ideal percentage of calories that should be ingested from carbohydrate, fat, or protein Macronutrient distribution for any given individual is based on the person’s current eating patterns, preferences, and goals Substituting low-glycemic-load foods (complex carbohydrates) for higher-glycemic-load foods may modestly improve glycemic control ​ Type II Diabetes Similar to Type I; requires comprehensive plan Patient should be screened and treated for hypertension, nephropathy, retinopathy, neuropathy, dyslipidemias Glycemic control with modified diet and physical activity; drug therapy ​ Monitoring Treatment Self-Monitoring of Blood Glucose (SMBG) Common target values for blood glucose ○ 80–130 mg/dL before meals ○ < 180 mg/dL one–two hours after meals Continuous glucose monitoring ○ Glucose monitoring with insulin pumps ​ Hemoglobin A1c Also called glycosylated hemoglobin or glycated hemoglobin Provides an index of average glucose levels over the prior two to three months A1c goal of below 7% is good for most patients Goal below 8% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, or advanced microvascular or macrovascular complications ​ Insulin Preparations: “High alert” agents Sources of insulin Recombinant DNA technology ○ Human insulin: Identical to insulin produced by the human pancreas  ○ Human insulin analogs: Modified forms of human insulin that have the same pharmacologic actions as human insulin but different time courses Short-duration: rapid-acting Insulin lispro Insulin aspart Insulin glulisine ​ Short-duration: slower-acting Regular insulin Intermediate duration Neutral protamine Hagedorn (NPH) insulin Insulin detemir ​ Long duration Insulin glargine Short-Duration, Rapid-Acting Insulin Insulin Lispro Used to control blood glucose levels after eating (post-prandial) Analog of human insulin Rapid onset Short duration Administered immediately before eating or even after eating Clear solution Rapid-acting analog of regular insulin Onset: 15–30 minutes after subcutaneous (subQ) injection Peak: 0.5–2.5 hours Duration: 3–6 hours Usual route is subQ via injection or use of an insulin pump Acts faster than regular insulin but has a shorter duration of action Should be injected 5–10 minutes before meals ​ Short-Duration, Slower-Acting Insulin Regular Insulin Unmodified human insulin Four approved routes: SubQ injection, subQ infusion, intramuscular (IM) injection (used rarely), and oral inhalation (approved but not currently used) Effects begin in 30 to 60 minutes Peak: 1–5 hours Duration: Up to 10 hours Clear solution ​ Intermediate-Duration Insulin Neutral Protamine Hagedorn (NPH) Drug is injected twice or three times daily to provide glycemic control between meals and during the night NPH insulin is the only one suitable for mixing with short-acting insulins Allergic reactions are possible NPH insulins are cloudy suspensions that must be agitated before administration NPH insulins are administered by subQ injection only  ​ Long-Duration Insulin Insulin Glargine [Lantus] Modified human insulin Prolonged duration of action (up to 24 hours) Once-daily subQ dosing to treat adults and children with Type I diabetes and adults with Type II diabetes Clear solution Never given IV ​ Insulin Appearance Except for NPH insulins, all insulins made in the United States are formulated as clear, colorless solutions ○ NPH insulin is a cloudy suspension Patients should inspect their insulin before using it and should discard the vial if the insulin looks abnormal ​ Concentrations 100 units/mL (U-100)—Most common concentration 200 units/mL (U-200) 300 units/mL (U-300) 500 units/mL (U-500) ​ Mixing Insulins NPH with short-acting insulins Short-acting insulin drawn first (clear before cloudy) Insulin pen injector and implantable insulin pump Administration Subcutaneous injection ○ Syringe and needle ○ Pen injectors ○ Jet injectors Subcutaneous infusion  ○ Portable insulin pumps ○ Implantable insulin pumps Intravenous infusion Inhalation Insulin injection sites - SQ Storage Unopened vials should be stored under refrigeration until needed Insulin should not be frozen Insulin can be used until the expiration date if kept in the refrigerator After opening, insulin can be kept up to one month without significant loss of activity Insulin should be kept out of direct sunlight and extreme heat Mixtures of insulin in vials are stable for one month at room temperature and for three months under refrigeration Mixtures in prefilled syringes should be stored in a refrigerator for at least one week; they should be stored vertically with the needle pointing up ​ Therapeutic Uses Principal indication is for diabetes mellitus (DM) ○ Required by all patients with Type I DM and by many patients with Type II DM ○ Most insulin sold is used by people with Type II diabetes, largely because Type II DM accounts for 90% to 95% of all cases of diabetes IV insulin for diabetic ketoacidosis Gestational diabetes Hyperkalemia: Promote uptake of potassium into the cells Aids in the diagnosis of growth hormone (GH) deficiency ​ Achieving Optimal Glucose Control Careful attention to all elements of the treatment program (diet, exercise, insulin replacement therapy) A defined glycemic target Dosing based on food intake, activity, stress Self-monitoring of blood glucose according to the patient’s individualized management plan A high degree of patient motivation Extensive patient education The responsibility for managing diabetes rests with the patient ​ Complications of Insulin Treatment Lipohypertrophy Hypoglycemia: Blood glucose below 70 mg/dL as insulin levels exceed needs Treatment ○ Blood glucose below 70 mg/dL Rapid treatment mandatory Conscious patients: Fast-acting oral sugar (for example, glucose tablets, orange juice, sugar cubes, nondiet soda) If swallowing reflex or gag reflex is suppressed: Nothing should be given by mouth; IV glucose or parenteral glucagon is the preferred treatment Lipohypertrophy Allergic reactions Hypokalemia Drug interactions ○ Hypoglycemic agents ○ Hyperglycemic agents ○ Beta-adrenergic blocking agents (mask symptoms of hypoglycemia) ​ Oral Antidiabetic Agents Biguanides—Metformin Sulfonylureas Thiazolidinediones (also known as glitazones)—Rosiglitazone, Pioglitazone Meglitinides (also known as glinides)—Repaglinide, Nateglinide ​ Biguanides—Metformin Mechanism of action ○ Inhibits glucose production by the liver ○ Increases glucose uptake in target tissue ○ Reduces glucose absorption in the gut Drug of choice for initial therapy in most patients with Type II diabetes ○ Used as monotherapy or in combination with other agents May delay the development of Type II diabetes in high-risk individuals Gestational diabetes—Compared favorably to insulin, but long-term effects are not known Contraindicated in renal insufficiency Adverse effects ○ Most common side effects: Gastrointestinal (GI) disturbances  ○ Vitamin B12 levels can be decreased and should be monitored ○ Lactic acidosis, a potentially fatal complication, is rare Drug interactions ○ Alcohol—Minimize intake to reduce lactic acidosis ○ Contrast dyes—Discontinue medicine one–two days before dye studies ​ Sulfonylureas First oral agent available ○ Used as monotherapy or in combination with other agents Mechanism of action ○ Promotes insulin release from the pancreatic islets ○ Can be used only for Type II diabetes ○ First-generation agents are older ○ Second-generation agents More potent and have lower doses Significant drug-drug interactions are less common and are milder ○ Second-generation agents are used due to these advantages Major side effects ○ Hypoglycemia Dose-dependent reduction of glucose levels Reduction occurs regardless of the glucose level—Therefore if the level is normal or low when administered, hypoglycemia will occur ○ Weight gain Drug interactions ○ Alcohol—Disulfiram-type reaction (palpitations, nausea)—Alcohol should not be consumed ○ Other medicines producing hypoglycemia ○ Beta-blockers—Masks hypoglycemic responses Thyroid Disorders and Pharmacology Thyroid Hormones Two major functions ○ Metabolism ○ Growth and development Promotes maturation in infancy and childhood Produces two active hormones whose synthesis is stimulated by low plasma levels of iodine ○ Triiodothyronine (T3) Synthetic T3: Liothyronine ○ Thyroxine (T4 tetraiodothyronine) Synthetic T4: Levothyroxine Actions  Increase in thyroid hormone levels: ○ Metabolic rate—Increases metabolism of target cells ○ Cardiovascular function—Increase in heart rate and contractility ○ Gastrointestinal function—Increased motility ○ Neuromuscular effects—Increased reactivity of the sympathetic nervous system and muscle tone ​ Thyroid Function Tests Serum thyroid-stimulating hormone (TSH) ○ Screening and diagnosis of hypothyroidism ○ Elevated TSH is an indicator of hypothyroidism Serum T4 test ○ Can measure total T4 or free T4 Serum T3 test ○ Can measure total T3 or free T3 ​ Two major dysfunctions: Hypothyroidism and hyperthyroidism Hypothyroidism Hypothyroidism is a severe deficiency of thyroid hormone. Cretinism (infancy)—Congenital hypothyroidism ○ Thyroid hormone is required for normal brain development ○ Treatment with replacement therapy with thyroid hormones Myxedema (adults)—Acquired hypothyroidism ○ From destruction or dysfunction of the thyroid ○ Replacement therapy with thyroid hormones; in almost all cases, treatment must co