Hypertension and Lipids

High density lipoproteins (HDL)

20% cholesterol Functions to remove cholesterol from cells and transport it to the liver where it is converted to bile acids

Statins

4-6 weeks for maximal lipoprotein changes Monitor LFTs initially then annually If experiencing myalgias-obtain CK: rhabdomyolysis fatigue, HA, petechiae, N, V, D LDL-C lowering potential Atorvastin> simvastatin>pravastatin=lovastatin>rosuvastatin>fluvastatin Lipitor> Zocor> Pravachol = Mevacor> Crestor> Lescol

Antihyperlipidemic agents

5 classes with distinct mechanisms of action: HMG-CoA reductase inhibitors Fibric acid sequestrants Selective cholesterol absorption inhibitors Nicotinic acid

Atherosclerosis

A type of arteriosclerosis Formation of intimal fibrous plaque with a central core rich in lipid Atherorha protrude into lumen, weaken the medial layer Affects elastic arteries, large and medium muscular arteries

What drugs are contraindicated for chronic hypertension during pregnancy?

ACE inhibitors ARBs DRI

PRILS

ACE inhibitors Captopril (capoten) Enalapril (Vasotec) Lisinopril (Prinivil, Zestril) Benazepril (Lotensin)

What is the site of action for verapamil and diltiazem?

Act on arterioles and on heart Negative inotropic effect

What is the site of action for dihydropyridines?

Act primarily on arterioles: vascular smooth muscle

What are the risk factors for hypertension?

Age: >60 Sex: middle age women have higher systolic BP Race: blacks are three times as likely to have severe hypertension as whites Genetic factors: familial tendency is apparent; gene locus for hypertension is near the locus that codes for angiotensin Sodium intake: higher correlation in salt sensitive people. In cultures with high sodium intake there is higher arterial blood pressure than in cultures with lower salt intake Calcium intake: higher levels of calcium intake correlate with lower levels of BP Alcohol intake: moderate ETOH has been beneficial effect; intake of more than 1 to 2 ounces more than 2 to 4 drinks a day; has harmful effect on BP Weight: weight gain increases BP; weight loss decreases BP; 1 mmHg drop for each 1.8kg of weight loss Diabetes mellitus: hypertension is secondary to diabetic nephropathy and microvascular changes in type 1. IN type 2, hypertension may be due to insulin resistance. High insulin levels may lead to SNS stimulation and endothelial effects Atherosclerosis: increased vessel stiffness increases vascular resistance Smoking: direct vasoconstrictor

Dihydropyridines

Agents that act mainly on vascular smooth muscle (Nifedipine (Adalat, Nifedical, Nifediac, Procardia) Significant blockade of calcium channels in blood vessels Minimal blockade of calcium channels in the heart

Spironolactone (Aldactone)

Aldosterone antagonists Mechanism of action: blocks aldosterone receptors; binds with receptors for other steroid hormones Therapeutic uses: hypertension; heart failure Adverse effects: Hyperkalemia Gynecomastia Menstrual irregularities Impotence Hirsutism Deepening of the voice

What are the therapeutic uses for nifedipine?

Angina pectoris Hypertension Investigational basis to relieve migraine headache and to suppress preterm labor

What are the therapeutic uses of verapamil (Calan, Isoptin)?

Angina pectoris: vasospastic angina and angina of effort Essential hypertension: first-line agent Cardiac dysrhythmias: atrial flutter, atrial fibrillation, paroxysmal supraventricular tachycardia Migraine

What are the adverse effects for angiotensin II receptor blockers?

Angioedema Fetal harm Renal failure: avoid in pts with renal artery stenosis Possibility of promoting cancer

What drugs act on the renin-angiotensin-aldosterone system RAAS?

Angiotensin-converting enzyme inhibitors: "prils" Angiotensin II receptor blockers: "sartans" Aldosterone antagonists

What are principal determinants of blood pressure?

Arterial pressure= cardiac output X peripheral resistance Cardiac out put: heart rate; myocardial contractility; blood volume; venous return

What are sympathetic nervous system blockers?

Beta-Blockers(antagonists) Combined Alpha and Beta blocker Alpha1-Blockers (antagonists) Alpha2-Agonists

Cholestyramine (Questran)

Bile acid sequestrant Mix powders with fruit juices or non carbonated fluid; to avoid absorption problems take 1 hour before or 3 hours after other medication GI side effects make patient compliance an issue: Bloating, nausea, constipation, burnt odor to urine Do not give with impaired intestinal function May reduce fat-soluble vitamin absorption Dose range: 4-16g

Bile Acid Sequestrants

Bind to bile acids, lowers intracellular store of cholesterol, increased catabolism of LDL, by liver; not absorbed systemically Major actions: Reduce LDL-C 15-30% Raise HDL-C 3-5% May increase TG Side effectsL GI distress/constipation; decreased absorption of other drugs They bind to bile acts, forming an insoluble complex and produce a large increase in the fecal excretion of bile acids. The decline in intracellular cholesterol leads to acceleration of HMG-CoA reductase activation, and uyregulation of LDL cell surface receptors

What are the angiotensin II receptor blockers (SARTANS)?

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 increase levels of bradykinin

What are the five direct hemodynamic effects of verapamil (calan) and diltiazem (cardizem)?

Blockade at peripheral arterioles: Reduces arterial pressure Blockade at arteries and arterioles of heart: Increases coronary perfusion Blockade at SA node: Reduces heart rate Blockade at AV node (most important): Decreases AV nodal conduction Blockade in the myocardium: Decreases force of contraction

What are the actions for diltiazem (cardizem)?

Blocks calcium channels in the heart and blood vessels (similar to verapamil) Lowers blood pressure Arteriolar dilation Direct suppressant/reflex cardiac stimulation = Little net effect on heart

What are the sites of drug action for antihypertensive mechanisms?

Brainstem Sympathetic ganglia Terminals of adrenergic nerves Beta1-adrenergic receptors on the heart Alpha1-adrenergic receptors on blood vessels Vascular smooth muscle Renal tubules Beta1receptors on juxtaglomerular cells Angiotensin-converting enzyme Angiotensin II receptors Aldosterone receptors

What damage occurs on target organs?

Cardiac: LVH: left ventricle hypertrophy Congestive heart failure Vascular disease: aneurysm; PVD Cerebral: stroke Renal: insufficiency; thrombosis Optic: blindness 2 hemorrhage

Pheochromocytoma

Catecholamines-secreting tumor induces resistance

How do you detect high cholesterol?

Cholesterol screening Every 5 years for adults over the age of 20 years Total cholesterol: HDL cholesterol: less than 40mg/dL (low to undesirable) LDL cholesterol: less than 100mg/dL (desirable) Triglycerides

Aliskiren (Tektuma)

Direct renin inhibitors Binds tightly with renin and inhibits the cleavage of angiotensinogen to angiotensin I Side effects: Angioedema cough GI effects, hyperkalemia fetal injury death

Cholesterol

Component of all cell membranes and membranes of intracellular organelles Required for synthesis of certain hormones and bile salts Deposited in stratum corneum of the skin Comes from dietary sources Manufactured by cells, primarily in the liver Increased dietary cholesterol produces only a small increase in cholesterol in the blood (inhibits endogenous cholesterol production)

What are the adverse effects of Verapamil?

Constipation: Most common complaint; Results from blockade of calcium channels in smooth muscle of the intestine; Especially severe for the elderly; Can be decreased by increasing dietary fiber and fluids Dizziness Facial flushing Headache Edemaof ankles and feet Gingival hyperplasia Heart block

Low density lipoproteins (LDL)

Contans 50% cholesterol They are the primary carrier f cholesterol to the tissues

Thiazide

Diuretic agents Initial choice for stage 1 HTN Promote Na and water excretion in kidneys Monitor for orthostatic changes; electrolyte abnormalities; acid base imbalances; hyperglycemia

What drugs do ACE 1 inhibitors interact with?

Diuretics Antihypertensive agents:Hypotensive effects are additive Drugs that raise potassium levels: May increase risk of hyperkalemia Lithium: May accumulate to toxic levels Nonsteroidal anti-inflammatory drugs: May reduce ACE I effects Note: ACE I should be avoided if K+ is > 5 mEg/L or serum creatinine is > 3 mg/dL No adverse effects on plasma lipids, glucose, sexual function Drug of choice in diabetes-related early stage proteinuria, contraindicated in pregnancy, not as effective in African-Americans

What are the drug interactions with verapamil?

DIgoxin Beta-adrenergic blocking agents

Total cholesterol levels

Desirable: Less than 200 mg/dL Borderline-high: 200 to 239mg/dL High" 240mg/dL

What are the drug interactions for diliazem?

Digoxin Beta-adrenergic blocking agents

What are the classifications of calcium channel blockers?

Dihydropyridines—Nifedipine (Procardia) Amlodipine (Norvasc): geriatric systolic hypertension Phenylalamine—Verapamil ( Calan) Benzothiazepine—Diltiazem(Cardizem)

What are the effects of Nifedipine?

Direct effects; Limited to blockade of Ca channels in vascular smooth muscle (VSM) No direct suppressant effects on: Automaticity, AV conduction, or contractile force Indirect effects: Lowered blood pressure (BP) activates baroreceptor reflex Primarily with fast-acting vs. sustained-release Vasodilation by blocking calcium channels: net effect: lowered blood pressure; increased heart rate; increased contractile force

What are classes of antihypertensive drugs?

Diuretics: thiazide diuretics; high-ceiling (loop) diuretics; potassium diuretics Sympatholytics (antiadrenergic drugs): beta-adrenergic blockers; alpha1 blockers; alpha/beta blockers (carvedilol and labetol); centrally acting alpha1 agonists; adrenergic neuron blockers; direct acting vasodilators (hydralazine and minoxidil); calcium channel blockers; drugs that suppress RAAS; ACE inhibitors; Angiotensin II receptor blockers; aldosterone antagonists; direct renin inhibitors

Progression of atherosclerosis

Droplets of fat in the blood stream are absorbed by the artery walls inducing the release of cytokines. Cytokines may cause the smooth wall of the artery to become sticky attracting inflammatory monocytes The monocytes squeeze between the endothelial cells, lining the intima, and turn into macrophages, gobble up fat and become foam cells Foam cells accumulate, forming an atheroma or plaque Inflammation thins the fibrous plaque's cap The cap ruptures, spilling the contents into the bloodstream, which attract platelets. A thrombus forms and occludes an artery causing a stroke or MI

How do you promote adherence?

Educate the patient Teach self-monitoring Minimize side effects Establish a collaborative relationship Simplify the regimen Other measures

What are the adverse effects of ACE inhibitors?

First-dose hypotension Fetal injury: category X Cough ( d/t bradykinin) Angioedema Hyperkalemia Dysgeusia(taste) and rash Renal failure Neutropenia

What are the adverse effects of nifedipine?

Flushing Dizziness Headache Peripheral edema Gingival hyperplasia Chronic eczematous rash in older patients Reflex tachycardia Increases cardiac oxygen demand Can increase pain for anginal patients Can be combined with a beta blocker for prevention of reflex tachycardia Note:Beta blockers decrease the adverse cardiac effects of nifedipine, but can intensifythe adverse cardiac effects of verapamil and diltiazem

What is the side effect of niacin (niaspan)?

Flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity Facial and upper extremity flushing may be decreased by taking ASA 325mg 30 minutes before niacin ingestion

Physiology of the renin angiotensin aldosterone system

Formation of angiotensin II by renin and angiotensin-converting enzyme (ACE) Renin: catalyzes the formation of angiotensin I from angiotensinogen Regulation of renin release Angiotensin-converting enzyme (kinase II): catalyzes the conversion of angiotensin I (inactive) to angiotensin II (highly active)

Trans fatty acids

Formed whem liquid fats are either hydrogenated or partially hydrogenated in order to make them solid at room temperature Foods high in trans fats are crackers, baked goods, cereals and breads to which these substances have been added to prevent them from becoming rancid The increase LDL's and reduce HDL concentrations

Cushing syndrome

Glucocorticoid excess mimics aldosterone effects

Arteriosclerosis

Hardening of the arteries Disease of small arteries and arterioles Luminal narrowing and fibrotic thickening of walls Primarily affects aorta, carotid, iliac, coronary, popliteal arteries

How does the renin-angiotensin aldosterone system regulate blood pressure?

Helps regulate blood pressure in the presence of hemorrhage, dehydration, or sodium depletion Acts in two ways: Constricts renal blood vessels Acts on the kidney to promote retention of sodium and water and excretion of potassium Tissue (local) angiotensin II production

What are the risk factors for hyperlipidemia and high levels of cholesterol?

Hereditary influences: Early heart disease (1st degree male <55; female <65) Age: (45 years or older for men; 55 years or older for women) Diet Obesity Cigarette smoking Lack of physical exercise Diabetes Mellitus Emotional stress Hypertension

What drugs are given for preeclampsia and eclampsia?

Hydralazine Magnesium sulfate (anticonvulsant)

What are the therapeutic uses for HMG-CoA reductase inhibitors?

Hypercholesterimia Primary and secondary prevention of CV events Post-MI therapy Diabetes

What are the therapeutic uses of angiotensin II receptor blockers?

Hypertension Heart failure Diabetic nephropathy: Significantly reduce level of protein uria and rate of renal decline in type 2 diabetes patients Myocardial infarction Stroke prevention Migraine headache

What are the therapeutic uses of ACE inhibitors?

Hypertension Heart failure Myocardial infarction (MI): Reduces mortality in post MI among patients with heart failure and diabetes Diabetic and non diabetic nephropathy: reduce rate of renal decline; reduces risk of progression to micralbuminuria in hypertensive type 2 diabetic patients Prevention of MI, stroke, and death in patients at high cardiovascular risk

Secondary hypertension

Identifiable primary cause Possible to treat the cause directly Some individuals can actually be cured Contraceptive use Renal disease Renal artery stenosis Cushing's syndrome Pheochromocytoma Pregnancy induced hypertension Hyperthyroidism, hypothyroidism

Cholesterol absorption inhibitor: Ezetimibe (Zeta)

Inhibits the absorption of cholesterol from dietary and biliary sources on the brush border of intestines Does not affect absorption of fat soluble vitamins

HDL cholesterol levels

Less than 40 mg/dL: a major risk factor for heart disease 40 to 59mg/dL: the higher your HDL, the better 60 mg/dL and above: this HD: is considered protective against heart disease

What are the contraindications of Niacin (Niaspan)?

Liver disease Severe gout Peptic ulcer

Hypothyroidism

Mainly diastolic HTN There is a reduction in CO; this is balanced by an increase in SVR, which produces elevated diastolic BP

Hyperthyroidism

Mainly systolic HTN Increased HR Increased strength of contraction

Amlodipine (Norvasc)

Mechanism: selective blockade of vascular Ca channels Main effect: vasodilatation; lower PVR; lower BP Adverse effects: headache flushing nausea ankle edema dizziness Use: Hypertension (more effective in African-Americans), angina. Not useful as an antiarrhythmic drug

What are examples of B1-selective (in low dose) beta-adrenergic blocking agents?

Metoprolol *Acebutolol Atenolol Betaxolol Bisoprolol Esmolol

Potassium sparing: Spironolactone (aldactone)

Modest diuretic effect; works distal tubules Monitor K levels

Fibric acid derivatives (fibrates)

Most effective drugs available for lowering TG levels: suppresses lipolysis in adipose tissue and inhibits triglyceride synthesis in the liver resulting in: Major actions: Lower LDL-C 5-20% Lower TG 20-50% Raise HDL-C 10-20% Can increase the risk for bleeding in patients on warfarin Can increase the risk for rhabdomyolysis in patients taking statins Three drugs in the United States: Gemfibrozil (Lopid) Fenofibrate (Tricor, others) Fenofibric acid (TriLipix)

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 Increased bone formation

What are the drug interactions with HMG-CoA reductase inhibitors (Statins)?

Most other lipid-lowering drugs (except bile acid sequestrants) Drugs that inhibit CYP3A4 Dosing should be once daily in the evening Endogenous cholesterol synthesis increases during the night Statins have greatest impact when given in the evening

What are the adverse effects of Ezetimibe?

Myopathy Rhabdomyolysis Hepatitis Pancreatitis Thrombocytopenia

What dihydropyridines produce greater blockade of Ca channels in the VSM than in the heart?

Nicardipine amlodipine isradipine felodipine nimodipine nisoldipine clevidipine

Primary (essential) hypertension

No identifiable cause, often genetic predisposition May have abnormalities in angiotensin gene. Basal total body nitric oxide production is reduced in patients with essential HTN Chronic, progressive disorder Population: older adults, African Americans, Mexican Americans, postmenopausal women Treated but not cured (lifelong condition) Referred to as "essential hypertension"

Triglyceride levels

Normal: <150mg/dL Borderline high: 150-199mg/dL High: 200-499 mg/dL Very high: 500 mg/dL or above

Beta-adrenergic blocking agents

OLOL Classification: Nonselective Cardioselective(b-1 selective) b-blockers with intrinsic sympathomimetic activity (ISA) Mechanism: Block cardiac b1 receptors lower CO; Block renal b1 receptors lower renin, lower PVR; Decrease SNS output

Selective alpha-1 adrenergic receptor blockers

OSIN Prazosin-minipres Terazosin-hydrin Doxazosin-cardura Mechanism: block a1 receptors in arterioles Main effects: decreased PVR-> decrease BP Adverse effects: 1st dose hypotension, fluid retention, dizziness, headache Use: used in moderate to severe HTN in combination with a diuretic and a Beta blocker

Fish oil supplements

Omega-3 polyunsaturated fatty acids decrease hepatic production of triglycerides by up to 45% HDL is unaffected; LDL may increase Fishy taste (freeze capsules), burping

LDL-Cholesterol Levels

Optimal: Less than 100mg/dL (goal for CV disease <70mg/dL) Near optimal/Above optimal: 100 to 129 mg/dL Borderline high: 130 to 159 mg/dL High: 160 to 189mmg/dL Very high: 190mg/dL and above

How do you individualize therapy?

Patients with comorbid conditions: renal disease; diabetes Patients in special populations: African Americans; children and adolescents; the elderly

What are examples of intrinsic (ISA) beta-adrenergic blocking agents?

Pindolol Acebutolol Penbutolol Cartelol Labetolol(a& b) Provide low level of cardiac stimulation-used in patients with bradycardia but not with MI

Nifedipine (Adalat, Procardia)

Vasodilation by blocking calcium channels Blocks in vascular smooth muscle Very little blockade of heart Ca channels Cannot be used to treat dysrhythmias

Calcium channel blockers

Prevent calcium ions from entering cells; inhibit Ca ion entry through L-type voltage gated channels Cause arteriolar dilation (decrease after load) Prevent coronary artery spasm Slow HR and decrease AV nodal conduction

What are examples of non-selective beta-adrenergic blocking agents?

Propranolol Timolol Nadolol Sotalo *Pindolol *Penbutolol *Cartelol *Labetolol(a& b) Carvedilol(a& b)

Chylomicrons

Rapidly removed from the blood

Nicotinic acid: Niacin

Reduces free fatty acid transport to liver and decreases synthesis of VLDL- this then reduces LDL Initial lowering 5-7 days with maximum effect 3-5 weeks Major actions: lowers LDL-C: 5-25% Lowers TG: 20-50% Raises HDL-C: 15-35% Niacin is believed to act on a hormone- sensitive lipase; this leads to inhibition of free fatty acids from adipose tissue ( lipolysis). The inhibition of lipolysis leads to reduced free fatty acid transport to the liver and therefore decreased synthesis of VLDL

What is the therapeutic use of Ezetimibe?

Reduces total cholesterol, LDL cholesterol, and apolipoprotein B Approved for mono therapy and combine use with statins

What are the actions of aldosterone?

Regulation of blood volume and blood pressure Pathologic cardiovascular effects

Renal artery stenosis

Renal artery obstruction by structure or atherosclerosis leads to chronic stimulation of RAAS

Pre-hypertension

SBP: 120-139 DBP: 80-89 Recheck in 1 year lifestyle modifications

Stage 1 hypertension

SBP: 140-159 DBP: 90-99 Treatment with 1 pill

Normal blood pressure

SBP: <120 DBP: <80 Recheck in 2 years

Stage 2 hypertension

SBP: >or= to 160 DBP: >or= to 100 Treat wit 2 pills

What are the toxic effects of Verapamil?

Severe hypotension Bradycardia and AV block Ventricular tachydysrhythmias

What are the adverse effects of diltiazem?

Similar to verapamil, except for less constipation Dizziness Flushing Headache Edema of ankles and feet

What are lifestyle modifications for hypertension?

Sodium restriction DASH (Dietary Approaches to Stop Hypertension) eating plan Alcohol restriction Aerobic exercise Smoking cessation Maintenance of potassium and calcium intake

Alpha2 Agonists

Stimulate alpha2 receptors in CNS results in decreased sympathetic flow (NE) Methyldopa (Aldomet) Clondine (Catapress)

What systems help regulate blood pressure?

Sympathetic baroreceptor reflex Renin-angiotensin-aldosterone system Renal regulation of blood pressure

Treatment of High LDL cholesterol

Therapeutic lifestyle changes (TLCs) Smoking cessation The TLC diet Exercise

Renin-angiotensin-aldosterone system

Throughout the body, it is a potent vasoconstrictor of arterioles. In the kidneys, it constricts glomerular arterioles, having a greater effect on efferentarterioles than afferent, raising systemic arterial blood pressure and decreasing the blood flow which forces blood to build up in the glomerulus, increasing glomerular pressure. Theglomerular filtration rate (GFR) is thus maintained, and blood filtration can continue despite lowered overall kidney blood flow. Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium reabsorption. In the adrenal cortex, it acts to cause the release of aldosterone. Aldosterone acts on the tubules (e.g., the distal convoluted tubulesand the cortical collecting ducts) in the kidneys, causing them to reabsorb more sodium and water from the urine. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood, potassium is secreted into the tubules, becomes part of urine and is excreted. Release of anti-diuretic hormone(ADH), also called vasopressin- ADH is made in the hypothalamus and released from the posterior pituitary gland. As its name suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate reabsorption of water in the kidneys. ADH also acts on the central nervous system to increase an individual's appetite for salt, and to stimulate the sensation of thirst.

Dietary considerations for High LDL cholesterol

Total fat <30% of total calories Saturated fat <7% of total calories Cholesterol <200mg Enough calories to maintain weight Increased viscous (soluble) fiber (10-25g/day) and plant stanols/sterols (2g/day) as therapeutic options to enhance LDL lowering

Very low density lipoproteins (VLDL)

Transport triglycerides from the liver to the plasma and then to the cells for storage (fat)

What are the fundamentals of hypertension drug therapy?

Treatment algorithm Initial drug selection: patients without compelling indications; patients with compelling indications Adding drugs to the regimen: rationale for drug selection; benefits of multi drug therapy Dosing Step-down therapy

What are the therapeutic uses for Diltiazem (cardizem)?

angina pectoris Hypertension Cardiac dysrhythmias Atrial flutter, atrial fibrillation, paroxysmal tachycardia