Anti-Hypertensives.pdf

Pharmacology 2 Exam 3 Lecture 1: Antihypertensive Agents Blood Pressure Classification • Normal: <120 and <80 • Prehypertension: 120-139 or 80-89 • Hypertension: >140/90 o Stage 1: 140-159 or 90-99 o Stage 2: >160 or >100 Essential Hypertension • 90-95% of HTN cases, the cause isn’t known • Symptoma...

Pharmacology 2 Exam 3 Lecture 1: Antihypertensive Agents Blood Pressure Classification • Normal: <120 and <80 • Prehypertension: 120-139 or 80-89 • Hypertension: >140/90 o Stage 1: 140-159 or 90-99 o Stage 2: >160 or >100 Essential Hypertension • 90-95% of HTN cases, the cause isn’t known • Symptomatic treatment, reduce BP • No true cure yet Known Causes of Secondary Hypertension • Sleep Apnea • CKD • Primary aldosteronism (Conn’s Syndrome) (Increase absorption of Na+, Decrease absorption of K+) • Renovascular disease • Chronic steroid therapy and Cushing’s Syndrome • Pheochromocytoma • Coarctation of the aorta (congenital narrowing) • Thyroid or parathyroid disease (too high production of hormones) Prevalence • More prevalent in men • Highest prevalence in elderly African-American females Complications • Cardiovascular System • CNS (strokes) • Renal System • Retinal Damage Organ Damage • Heart o Left ventricular hypertrophy (over-growth) o Coronary artery disease o Myocardial infarcts o Heart failure • Brain o Stroke or TIA Risk Factors • Obesity (big risk) • Stress (type A personalities) • Lack of exercise • Diet (excess dietary salt) • Alcohol intake/Cigarette smoking Most Important Peripheral Organ for BP: Kidney/Adrenal Gland BP Goals • <140/<90 and lower if tolerated • <130/<80 in diabetics • <130/<85 in cardiac failure • <130/<85 in renal failure • <125/<75 in renal failure w/ proteinuria > 1.0g/24 hours Lifestyle Modifications • Reduce weight to normal BMI: 5-20mmHg/10kg loss • DASH (Dietary Approaches to Stop Hypertension): 8-14 mmHg, Emphasizes fruits, veg, low fat dairy foods, and reduce sodium intake • Dietary Sodium Reduction: 2-8 mmHg • Increase Physical activity: 4-9 mmHg • Reduce alcohol consumption: 2-4 mmHg Initial Drug Choices • With Compelling Indications o Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) • Without Compelling Indications o Stage 1 Hypertension: Thiazide-type diuretics for most § May consider ACEI, ARB, BB, CCB, or combination o Stage II Hypertension: 2-drug combo for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Mean Arterial Pressure • MAP=DP + 1/3(SP-DP) • SP=CO=HR*SV • DP=SVR Diuretics • Used alone or in combination w drugs from other groups • Can be used as initial TX • Adverse effects: renin secretion due to volume and Na Depletion • Thiazides: chlorothiazide, hydrochlorothiazide • Loop Diuretics: furosemide, bumetanide, ethacrynic acid • Potassium sparing diuretics: spironolactone, triamterene, amiloride • Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) o Diuretics have been as effective as other agents in the prevention of cardiovascular complications associated to HTN o Diuretics enhance the efficacy of other agents in multidrug regimens o They are cost effective Agents that Inhibit Adrenergic Transmission • Reserpine o Mechanism: depletes NRTM (NE, DA, 5HT) in the storage vesicle of the central and peripheral nerve endings o Main effects: depress NE function centrally and peripherally à decreases HR, contractility, and PVR (causes vasodilation due to suppression of NE) o Also used as an antipsychotic (stops Dopamine dumping) o Adverse Effects: depression, orthostatic hypotension (changes in pressure due to posture, standing drops BP), dry mouth, impotence o Pharmacokinetics: onset is slow, gradient effect (not used for emergencies bc slow) o Rarely use for HTN • Guanethidine o Mechanism: depletes the nerve ending of the NE in the PNS (peripherally and only nerves w NE) Main Effect: Decrease in PVR and decrease in HR à decrease in BP Adverse effects: orthostatic hypotension, Na+ and water retention (bc vasodilation); no CNS effects (causes depletion but there is an initial surge of NE, can cause cardio problems) o Pharmacokinetics: Poorly absorbed from the GI, onset is slow (1-2 weeks). Metabolites excreted in urine o Not used anymore because of the severe side effects Selective Alpha-1 Adrenergic Receptor Blockers • Prazosin-Minipress, Terazosin-Hytrin (used for BPH-Benign Prostate Hyperplasia), Doxazosin-Cardura o Favorable influence on serum lipid levels and no interference with glucose metabolism o Mechanism: block alpha1 receptors in vasculature (BPH: arteriolar vasodilation) (blocks innervation of NE and their receptors so bladder sphincter gets loose so patient can pee) o Main effects: decrease PVR à decrease BP o Adverse effects: 1st dose phenomenon (dramatic pressure drop), fluid retention (edema), dizziness, headache o Pharmacokinetics: t1/2=4.5 hours o Used in stage 1 and stage 2 HTN in combo regimen Beta-Adrenergic Blocking Agents • Classification o Nonselective (1st generation) (some w intrinsic sympathomimetic activity (ISA)) § ISA: b-1 activated at heart, accelerate HR, blocking causes decrease HR. b-2 causes vasodilation in peripheral arteries, and bronchodilation in the lungs, blocking them causes constriction in peripheral arteries and bronchi. Asthmatic & diabetic patients may be a bad idea for these patients. Mask hypoglycemic effects that insulin causes in diabetics. o Cardio-selective (b-1 selective, 2nd generation) o Hybrid antihypertensive drugs (Beta and Alpha blocking CV actions) (3rd generation) • Proposed Mechanisms o Block cardiac beta1 receptors à lower HR à lower CO o Block renal beta1 receptors à low renin, lower PVR (at level of kidneys causes lower production of renin, causing constriction) o Oppose action of NE Released (ISA) (releases, but opposes what it releases) • 1st Generation Non-Selective o Propranolol o Timolol (hydrophilic) o Pindolol* o Penbutolol* o Carteolol* nd • 2 Generation B1-Selective (good for diabetics and asthmatics) o Metoprolol o Acebutolol* o Atenolol (hydrophilic) o Betaxolol o Bisoprolol rd • 3 Generation (Hybrids) o Labetalol (alpha and beta*) (used in emergency rooms to lower BP in hypertensive crisis) o Carvedilol (alpha and beta) (blocker of choice for CHF, decrease HR and PVR) • Propranolol (Inderal) o Mechanism § Block cardiac B-1 Receptors à lower CO o o § Block renal B1 Receptors à lower renin, lower PVR Main effects: decrease HR and PVR Adverse effects: bradycardia, mental depression (decreases 5HT levels), B2 blockade in airways, glucose and lipid metabolism, vasoconstriction in extremities o Pharmacokinetics: 30-50% metabolized in the first pass in the liver. T1/2 3-5 hours, slow release (extended release) available o Uses: used in stage 1 and 2 HTN alone, or in combination o Drug Interactions: (be cautious w other meds that slow the heart) verapamil (angina medication), diltiazem, digitalis (these cause AV block) • Labetalol (Trandate) o A combined alpha-1, beta-1, and beta-2 blocker. o Beta blocking action is more prominent o Also has ISA property o Can be given IV for hypertensive emergencies • Carvedilol (Coreg) o Nonselective beta blocker and alpha 1-blocker o BB choice in the treatment of CHF Agents that act on the CNS • a-Methyldopa (Aldomet), clonidine (Catapres) (ER) o Mechanism: central alpha-2 agonist in brain (alpha-2’s are inhibitory) (agonist effect inhibits system), suppress sympathetic adrenergic activity o Main effect: decrease PVR and HR o Adverse effects: sedation, drowsiness, dry mouth, impotence, bradycardia; false (+) Coombs’ antiglobulin test (measures antibodies against RBC, hemolytic anemia) o Pharmacokinetics: oral or parenteral, transdermal; T1/2=2hr o Used for stage 1 and 2 HTN Vasodilator Drugs • Calcium entry blockers (nifedipine and others) • Potassium channel openers (minoxidil, diazoxide iv) • Direct acting vasodilators (hydralazine, Na-nitroprusside iv) • Common adverse effects due to fall in BP: o Reflex tachycardia (caused by excess dilation) o Elevate reninàNa/H2O retention (aldosterone and angiotensin cause pressure and retention) Calcium Channel Blocker • Mechanism: inhibit Ca entry through L-type voltage gated channels (L-type cause a surge for action potentials) • Non-Dihydropyridines o Act primarily on the heart (vasodilation and decrease HR) o Phenylalkylamines: verapamil- negative inotropic/chronotropic and coronary vasodilatory effect o Benzothiazepines: diltiazem- negative chronotropic and coronary and peripheral vasodilatory effect (mild, periphery) • Dihydropyridines (DHP) o Nifedipine, amlodipine o Act on peripheral vascular system (vasodilation) o May cause reflex tachycardia o Ankle edema (peripheral edema) • Nifedipine (DHP) o Mechanism: selective blockade of vascular Ca channels o o Main effect: vasodilation à lower PVR à Lower BP Adverse effects: headaches, ankle edema, dizziness, reflex tachycardia with short acting version (now have Procardia SR) o Use: Hypertension (more effective in African-Americans), angina o Not effective as an antiarrhythmic drug • Verapamil and Diltiazem (N-DHP) o Mechanism: blockade of Ca channels in § Heart muscle and the AV node (pitstop for electrical conduction) § Vasculature (diltiazem) o Main effects: decrease HR and HC à decrease CO and coronary vasodilatory; decrease PVR (diltiazem) o Adverse effects: similar to DHP but NO Reflex Tachycardia o Drug interaction: caution for AV block w beta blockers, and digitalis (cardio glycosides-negative inotropic effect) o Uses: HTN, Angina, Arrhythmias Potassium Channel Openers • Minoxidil (Loniten), Diazoxide (Hyperstat IV, Pinacidil) • Mechanism: open K-channels of vascular smooth muscle cells à K-efflux à hyperpolarization à vasodilation • Main Effect: vasodilation à lower PVR à lower BP • Adverse effects: reflex tachycardia, Na and fluid retention; hyperuricemia, hyperglycemia (Diazoxide) • Uses: Diazoxide IV in hypertensive emergencies Direct Acting Vasodilators • Na-nitroprusside IV (Nipride) o Mechanism: metabolite is nitric oxide à cGMP. NO is rapid acting venous and arteriolar vasodilator o Main effect: vasodilation à lower PVR à lower BP o Adverse Effects: reflex tachycardia, severe Hypotension, possible cyanide poisoning o Pharmacokinetics: rapid acting, short plasma half life o Use: hypertensive emergencies Agents that Affect RAAS • ACE Inhibitors: captopril, enalapril, lisinopril • Angiotensin II receptor blockers (ARB): losartan, valsartan, irbesartan RAAS • Maintenance System of kidney, controls BP • Angiotensinogen- produced in liver, goes into blood. When exposed to renin at the liver, it converts to Angiotensin I. • ACE (angiotensin converting enzyme-produced in the lungs and kidneys): converts angiotensin I to angiotensin II • Angiotensin II: vasoactive substance, several activities o Increases sympathetic activity leading to vasoconstriction o Causes reabsorption of Na and Cl, excretion of potassium, and H2O retention in the tubular area § Water follows sodium o Excites the adrenal gland cortex producing aldosterone (causes reabsorption of sodium and excretion of potassium) o Activation of the pituitary gland, causing excretion of ACTH which activates ADH (anti-diuretic hormone) which decreases urination • Signaling of too much vasodilation activates renin secretion o o ACE Inhibitors • Captopril (Capoten), Enalapril (Vasotec), Lisinopril (Prinivil), Ramipril (Altace) o No adverse effects on the plasma lipids, glucose, or sexual function o Drug class of choice in diabetes-related early-stage proteinuria (excessive protein in urine) o Contraindicated in pregnancy o Not as effective in African Americans • Mechanism: inhibit ACE à low circulating Ang II (acts on ang I) à decrease PVR • Main Effects: decreased PVR à decreased BP • Adverse effects: skin rash, taste, cough, hyperkalemia (too much potassium in system) • Pharmacokinetics: half-life= 3, 11, 12 respectively • Use: stage 1 and 2 HTN; CHF Angiotensin II receptor blockers (ARB) • Losartan-Coozar, Valsartan-Diovan, Irbesartan-Avapro, Candesartan-Atacand • Mechanism: selectively block Ang II AT-1 receptor à decrease PVR à decrease BP • Adverse effects: no cough, very few adverse similar to ACE inhibitors