DIURETICS Drug Name Thiazides Examples Chlorothiazide (Diuril) Hydrochlorothiazide (hydroDiuril, Esidrix) MOA Inhibits the Na+/Cl- (NCC1)

cotransporter keeping Na+ in the lumen, H2O follows Target Distal tubule Oral Also used for Ca2+ reabsorption Contraindication/Side Effects Sulfa drug allergy, hypokalemia, hyponatremia, hypomagnesia, metabolic alkalosis, hyperglycemia, hyperuricemia, volume depletion, increased blood lipids (Natriuresis effect moderate) NSAIDs decrease effectiveness by reducing GFR and delivery to urine Decrease anticoagulant activity

Thiazide-like Diuretics Loop Diruetics

Chlorthalidone (Hygroton) Indapamide (Lozol) Metolazone (Zaroxolyn) Furosemide (Lasix, furoside) Bumetanide (Bumex) Torsemide (Demadex) Ethacrynic acid (Edecrin)

Oral & IV

Inhibits Na+/K+/Clcotransporter at the Cl- site.

Thick ascending limb of loop of henle Oral & IV Promotes Ca2+ excretion

Potassium sparing diuretics

Osmotic Diuretics

Amiloride (Dyrenium) Triamterene (Midamor) Spironolactone (Aldactone) Eplerenone (Inspra) Glycerol Mannitol

Increases K+ reabsorption

Collecting duct For heart failure

Sulfa allergies. Blood cell deficiencies, hearing impairment, Ca++, Mg++, K++, and H+ excretion, metabolic alkalosis, vascular volume depletion, hyperglycemia and hyperuricemia. EA not sulfa drug, but most ototoxic. F&T raise blood lipids, glucose, and uric acid Aminoglycoside antibiotics Amphotericin B (antifungal) Cisplatin (anticancer) Tenofavir (anti-HIV) NSAIDs decrease effectiveness by reducing GFR and delivery to urine Loops increase anticoagulant activity Hyperkalemia, metabolic acidosis.

Carbonic

Acetazolamide

Draws fluid out of tissue into plasma. Flush toxins from kidney Inhibits carbonic

Act very quickly, used in emergencies only. For cerebral edema, pulmonary edema, acute glaucoma, renal failure

Proximal tubule

Used for glaucoma, altitude sickness, and alkalinization

Anhydrase Inhibitors

anhydrase, increases excretion of bicarb

of urine. Inhibits excretion of drugs that are weak bases (amphetamines, ephedrine, quinidine). Hypokalemia, hyperglycemia, hyperchloremia, metabolic acidosis, drowsiness.

ANTIHYPERTENSIVES
Drug Classification I. Diuretics Thiazide and loop diuretics Potassium-sparing diuretics II. Sympatholytics -Adrenergic receptor antagonists -Adrenergic receptor antagonists Centrally acting drugs Decrease No change or decrease No change or increase Decrease No change or increase No change or decrease Increase* No change or decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Increase Increase No change or decrease No change or decrease Peripheral Vascular Resistance Cardiac Output Blood Volume Plasma Renin Activity Left Ventricular Hypertrophy

Decrease

No change or decrease

Decrease

Decrease

III. Angiotensin inhibitors Angiotensin-converting enzyme inhibitors Angiotensin receptor antagonists Decrease Decrease No change or increase No change or increase No change No change or increase Increase Increase Decrease Decrease

IV. Ca channel blockers/Vasodilators Calcium channel blockers Decrease No change or increase No change No change or increase Decrease

Other vasodilators Hydralazine Minoxidil Nitroprusside Decrease Decrease Decrease Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase No change or increase

Antiangiotensin
Drug ACE inhibitors Sulfahydryl Containing ACEIs Dicarboxyl contiaining ACEIs Examples Captopril Benazapril (Lotensin) Enalapril (Vasotec) Enalaprilat (Vasotec injection) Lisinopril (prinivil/zestril) Moexipril (Univasc) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Fosinopril Candesartan (atacand) Eprosartan (Teveten) Irbesartan (Avapro) Losartan (Cozaar) Olmesartan (Benicar) Telmisartan (Micardis) Valsartan (Diovan) Mechanism Prevents angiotensin I to becoming active angiotensin II Administration / Interactions Lasts for 24 hours except captopril (6 12 hours) Antacids reduce availability Capsacin worsens dry cough NSAIDS reduce antihypertensive response K+ sparing diuretics worsen hyperkalemia Advantages Reduces diabetic nephropathy Disadvantages Hypotension, dry cough (accumulation of bradykinin in lungs), hyperkalemia, teratogenic, skin rash, angioedema, swelling of mouth, nose, throat, lips, tongue, renal failure. DO NOT GIVE IN RENAL ARTERIAL STENOSIS, altered tasted, hepatotoxicity

Phosphorus containing ACEIs Antiogensin Receptor Blocker (ARB)

Blocks angiotensin II from activating AT1 receptors and causing aldosterone release

Irbesartan and losartan approved for diabetic nephropathy Losartan for stroke prophylaxis Valsartan for heart failure patients intolerant to ACIs

Permit activation of AT2 receptors. Does not increase bradykinin levels. Less angioedema

Teratogenic, hyperkalemia in patients with renal insufficieny. DO NOT GIVE IN RENAL ARTERIAL STENOSIS!

Antihyperlipidemics
Drug HMG-CoA Reductase Inhibitors (the Statins) Examples Atrovastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) Mechanism Blocks HMG-CoA reductase from converting HMG-CoA mevalonic acid. Rate limiting step in cholesterol synthesis Less cholesterol synthesis, upregulation of LDL receptors, increased uptake of LDL from blood, decreased VLDL secretion from liver Bind to bile acids in gut and are excreted in feces blocks enterohepatic cycling of bile acids liver cholesterol consumed for making bile acids LDL receptors upregulated blood LDL reduced Blocks cholesterol transporting protein (NPC1L1) in brush border cells and from micelles into enertocytes. Activate peroxisome prliferator activated receptor (PPAR-) increase LPL, oxidation of fatty acids, and decrease apolipoprotein C-III (inhibitor of LPL). Increases removal of VLDL and chylomicron triglycerides Inhibition of lipase Increase Apolipoprotein A-I Used for Hypercholesterolemia, Atocastatin and rosuvastain for lowering triglycerides or mixed hyperlipidemia, children with familial hypercholesterolemia, reduce risk of CHD, mortality rate, osteoporosis and cancer Hypercholesterolemia, diarrhea and itching caused by excessive bile acids Advantages Improved endothelial function, increased stability of atherosclerotic plaques, anti-inflammatory, inhibition of lipoprotein oxidation, anticoagulation. Well tolerated Very safe Side Effects Toxicity in small percentage, GI problems (most common) Rhabdomyolysis - Most serious. myopathy MUST DISCONTINUE, at risk are older, female, renal or hepatic disease, hypothyroid, and drugs that inhibit statin metabolism. DO NOT GIVE IN PREGNANCY, DO NOT GIVE erythromycin and itraconazole. GI disturbances, skin rash, might slightly increast TGs, can bind to digoxin, thyroxin, and warfarin and reduce their effects

Bile Acid Sequesterants

Colesevetal (Questran) Colestipol (Colestid) Colestyramine (Welchol)

Cholesterol Absorption Inhibitors

Ezetimbe (Zetia)

Hypercholesterolemia, homozygous familial hypercholesterolemia

Well tolerated. Best if in combination with a statin (simvastatin)

Impaired liver function, dyspepsia, myalgia, myopathy (rare), headache

Fibrates

Fenofibrate (Lopid) Gemfibrozil (Tricor)

Hypertriglyceridemia, Low HDL

Can combine with statins

GI disturbances, myopathy (rhadbdomyolysis)

Niacin

Nicotinic Acid Vitamin B3

Hypertriglyceridemia, decrease triglycerides (VLDL), LDL-C, and increases HDL-C. Mixed hyperlipidemia, hypercholesterolemia

Most effective drug for raising HDL. Well tolerated. Pruritis can be controlled with aspirin

Flushing, pruritis (high prostaglandins), hyperuricemia gout, impaired insulin sensitivity (aggravate diabetes), hepatic injury, peptic ulcer. AVOID in patients with DIABETES, PEPTIC ULCER, or HEPATIC INJURY

Calcium Channel Blockers

Drug Endothelin Receptor Antagonists Ca++ Channel Blockers Examples Bosentan Mechanism Blocks endothelin from activating endothelin receptors and vasoconstricting Blocks calcium channel type L in smooth muscle cells and myocytes. Cause vasodilation. Dihydropyradines: No effect on heart Others: Affect heart. Decrease SA node automaticity, AV node conduction velocity, and cardiac contractility (negative ionotropic effect/reduces cardiac contractility Used for Pulmonary HTN Side Effects

K+ Channel Openers

Dihydropyridines : Amlodipine (Amvaz/Norvasc) Felodipine (Plendil) Isradipine (DynaCirc) Nicardipine (Cardene) Nifedipine (Adalat / Procardia) Nimodipine (Nimotop) Nisoldipine (Sular) Phenylalklamines: Verapamil (Calan/Isoptin) Benzothiazepine: Diltiazem (Cardizem) Diarylaminopropylamine ether: Bepridil Minoxidil (Loniten) Cromakalim Pinacidil Nicorandil Sildenafil (Viagra) Amrinone (inamrinone) Milrinone (Primacor)

HTN, angina (Amlo, Felo, Nicar, & Nifed for stable angina), arrhythmias (verapamil & diltiazem), subarachnoid hemorrhage (nimodipine), prophylaxis of migraine (verapamil)

Fatigue, headache, dizziness, flushing, peripheral edema, gingival hyperplasia, reflex tachycardia (dihydropyridines), arrhythmias, reduced clearance of digoxin. Verapamil and Diltiazem CONTRAINDICATED IN ACUTE HEART FAILURE

Direct vasodilation by opening ATP-sensitive K+ channels, act on arterial smooth muscle, decreases arterial blood pressure Prevent hydrolysis of cGMP and cAMP by phosphodiesterase. Sildenafil inhibits PDE5 in corpus cavernosum Others inhibit PDE3 in cardiac muscle, vascular smooth muscle Biotransofrmation into NO cGMP formation vasodilates smooth muscle in vasculature, reduces preload, decreases ventricular wall tension, dilates coronary arteries Spontaneously releases NO vasodilates smooth muscle in vasculature Unclear. Relaxes smooth muscle.

HTN, baldness (minoxidil)

Headache, hypertrichosis (excessive hair growth). Should be used with diuretics/ blockers to prevent fluid retention and reflex tachycardia. DO NOT GIVE NITROGLYCERINE TO PATIENTS WHO HAVE USED VIAGRA WITHIN 24 HOURS

Phosphodiesterase inhibitors (PDEI)

Sildenafil for ED Others for heart failure

Organic Nitrates

Nitroglycerine Isosorbide dinitrate (Isordil) Isosorbide mononitrate (Ismo)

Angina pectoris

Nitroprusside

Sodium Nitroprusside (Nitropress)

IV infusion for hypertensive emergencies Combine with venodilating agents (nitrates). Moderate severe HTN, Heart failure IV administration for HTN emergencies

Others

Hydralazine (Apresoline)

Fenoldopam (Corlopam)

Dopamine D1-like receptor agonist Vasodilation

Excessive vasodilation, hypotension, reflex tachycardia, headache, dizziness DO NOT GIVE NITROGLYCERINE TO PATIENTS WHO HAVE USED VIAGRA WITHIN 24 HOURS Metabolism turns it into cyanide and can cause poisoning in patients with renal insufficiency after prolonged administration Headache, hypotension, reflex tachycardia, lupus-like syndrome (arthralgia, arthritis, fever) Excessive vasodilation

Sympatholytics

Drug -blockers

Examples

Where it works

How it works

Osins are selective, Phens are nonselective Alf & Tami have prostate problems PHEN treat PHEO

Doxazosin Prazosin Terazosin Alfuzosin Tamusulosin (flomax) Phenoxybenzamine

Competitive at 1

Competitive at 1, bladder specific Non-competitive (irreversible) at 1 and 2 Competitive 1 and 2

Vasodilation, decreases vascular resistance and BP. Relaxes bladder neck and prostate Relax bladder neck and prostate Vasodilation and decreased vascular resistance and BP Vasodilation and decreased vascular resistance and BP

Conditions NOT PREFERED FOR INITIAL TREATMENT OF HTN Hypertension, BPH

Side Effects

Hypotension, syncope. Do not cause reflex tachycardia as much as phens.

Benign prostate hyperplasia

Hypertension due to pheochromocytoma Hypertension due to pheochromocytoma For necrosis and ischemia after injection of agonists

Hypotension, reflex tachycardia Hypotension, reflex tachycardia. Not useful for chronic HTN because of side effects Bronchoconstriction (DO NOT GIVE TO ASTHMATICS), Slows blood sugar recover after insulin injections (USE WITH CAUTION IN TYPE I DIABETES)

Phentolamine

Blockers A-M = 1 only N Z = 1 & 2 Timolol Nadolol Pindolol Propranolol 1 and 2 1 and 2 1 and 2, ISA & MSA 1 and 2 MSA

Decreased cardiac rate, output, AV conduction, O2 demand, BP + decreased intraocular pressure Same as all -blockers + High lipid solubility. Higher incidence of CNS crisis

Hypertension, acute MI, CHF, migraine, glaucoma Hypertension, angina, migraine, Parkinsonian tremor Hypertension only Hypertension, angina, arrhythmias, hypertrophic subaortic stenosis, essential tremor, migraine, acute thyrotoxicosis, acute MI, pheochromocytoma

Acebutolol Atenolol

1 and 2, ISA & MSA 1 blocker 1 blocker 1 blocker with MSA

Same as all -blockers

Hypertension, cardiac arrhythmias Hypertension, angina, acute MI Water soluble, limited penetration of CNS less CNS side effects

Esmolol Metoprolol

IV for perioperative HTN, Acute SVT Hypertension, angina, acute MI (but NOT MI with moderatesevere heart failure!). Chronic heart failure. SVT HTN, CHF when combined with ACEI and diuretics Insomnia and Depression, negative ionotrope, bronchospasm

Bisoprolol & blockers

Highly selective 1 blocker

Antioxidant activity, K+ channel activators, increased NO Vasodilation, lower HR and BP, increased cardiac output, antioxidant Vasodilation, decreased HR and BP

Carvedilol

1, 2, and 1 blocker 1, 2 with MSA, and 1 blocker

Hypertension, heart failure

Labetolol

IV for HTN emergencies Oral for chronic HTN

Liver injury

Gq Gi Go

Epi > NE >> Iso Phenylephrine/prazosin

Vascular smooth muscle Genitourinary smooth muscle Intestinal smooth muscle Heart Liver

Contraction, increased blood pressure Contraction Relaxation Increased inotrophy and excitability Glycogenolysis and gluconeogenesis

Gi Go

Epi>NE>Iso Clonidine/Yohibine

Pancreatic cells Platelets Nerve Vascular smooth muscle Heart Heart Renal Juxtaglomerular Cells Smooth Muscle (Vasc., Bronchial, GI, GU) Liver Skeletal Muscle Adipose

Decreased insulin secretion Aggregation Decreased NE release Contraction Chronotropy & Inotropy AV node conduction velocity Renin secrettion Relaxation Glycogenolysis & gluconeogenesis Glycogenolysis & K+ uptake Lipolysis, thermogenesis,may be linked to obesity and type II diabetes?

Gs

Iso>Epi=NE Dobutamine/ Metoprolol

Gs

Iso>Epi>>NE Terbutaline/ ICI118551

Gs

Iso=NE>Epi

Antiarrhythmics Class I Na+ Channel Blockers Bind to Na+ channels, when channels are in open (activated) and inactivated states Use-dependent blockage More effective on tissue that is firing rapidly Class IA: Quinidine Procainamide Disopyramide Class IB: Lidocaine Mexiletine Tocainide Class IC: Flecainide Propafenone Class II -Blockers Inhibit sympathetic activation of cardiac automaticity and conduction Slow heart rate, decrease AV-node conduction velocity, increase AV node refractory period Esmolol Metoprolol Propranolol Class III K+ Channel Blockers Prolong action potential duration and refractory period Class IV Ca2+ Channel Blockers Decrease AV node conduction velocity and increase AV node refractory period

Amiodarone Ibutilide Dofetilide Sotalol

Diltiazem Verapamil

Drug Na+ Channel Blockers Class IA

Examples

Quinidine

Procainamide

Disopyramide

Mechanism Bind to Na+ channels when they are open and inactive. Greater affinity for open state, slow dissociation. Increases threshold potential, decreasing conduction velocity, and increases refractory period. Blocks K+ channels prolonging action potential and refractory period. Atropine-like effects, inhibit parasympathetics. Disopyramide > quinidine > procainamide. Most pronounced effects. Effect tachycardia more than NSR Reduces 0 phase and slows phase 4 depolarization.

Used for

Advantages/Disadvantages

Fever, malaria, rarely for arrhythmias (SVT and ventricular). Vagolytic effects increase AV nodal conduction, use with a BB (verapamil) Suppression of SVT and ventricular arrhythmias. 2nd choice to lidocaine. Convert SVT to NSR

GI, diarrhea, torsades de pointes (in people with QT prolongation, contraindicated), thrombocytopenia, cinchonism (tinnitus, dizziness, blurred vision), digoxin toxicity, contraindicated in QT Lupus-like syndrome, peripheral vasodilation. Does not affect digoxin level Anti-cholinergic effects, negative ionotrope. Contraindicated in obstructive uropathy, glaucoma, uncompensated CHF.

Class IB

Lidocaine (Xylocaine)

Class IC

Beta Blockers K+ Channel Blockers

Ca++ Channel

Not very effective for SVT because they are from non-ischemic tissue. CNS effects (nervousness, tremor, paresthesia) Mexiletine (Mexitil) administered orally long term Tocainide can lead to agranulocytosis Tocainide (reduction in number of basophils, neutriphils, and eosinophils) and other blood deficiencies. Flecainide (Tambocor) Greater affinity for open state, very slow SVT and life-threatening Flecainide SA dysfunction, decreased Propafenone (Rythmol) rate of dissociation. Most potent. ventricular arrhythmias conduction, conduction blockage Propafenone: Can induce arrhythmias, blood abnormalities. Most frequently used drugs for SVT and ventricular arrhythmias caused by sympathetic stimulation. Reduce mortality. Most useful antiarrhythmics. Prolong action potential duration and refractory period. Reduce re-entry. Amiodarone (Cordarone) Slows ventricular conduction velocity, 1st choice for A-Fib. A-Flutter, Hypotension, AV block, arrhythmias, affects rate of phase 0 depolarization. SVT, and life-threatening, thyroid abnormalities, liver toxicity, lung Blocks K+, Na+, Ca2++ channels and sustained ventricular tachycardia. fibrosis and pneumonia, increases digoxin receptors and other drugs. Infrequently prolonged QT torsades de poites Ibutilide (Corvert) Prolong action potential duration and Rapid conversion of A-Fib/Flutter, Torsades de Points due to prolonged QT. Dofetilide (Tikosvn) refractory period. Reduce re-entry. maintain sinus rhythm in A-Fib Sotalol (Betapace) Blocks K+ channels and -receptors Ventricular arrhythmias, atrial Torsades de Points due to prolonged QT arrhythmias including A-Fib. Bronchospams due to BB effect Diltiazem Act on SA and AV nodes, slow conduction. SVT, acute paroxysmal SVT Hypotension (especially if mistakenly given

but has high affinity for both and fast dissociation.

Drug of choice for V-Tach and VFib after cardioversion in setting of acute ischemia. Suppression of ventricular arrhythmias

Blockers

(Cardizem/Dilacor) Verapamil (Calan/Isoptin) Adenocard

Adenosine Digoxin Mg Sulfate

Prolong repolarization and refractory of AV. Little effects on Na+ dependent tissues (Purkinje fibers, atrial/ventricular muscle). Reduce ventricular rate. Rapid IV bolus, short half life, 10 seconds

(PSVT). Reduce ventricular rate in A-Fib/Flutter with rapid ventricular response. PSVT Slows ventricular rate in A-Fib

to V-Tach patients), AV blockage, increase digoxin levels

Increases vagal tone, slows AV conduction and increases AV refractory. Suppress drug-induced torsades de poites by shortening Q-T interval Treat digoxin-induced arrhythmias SVT caused by Mg deficiency

Headache, flushing, chest pain, excessive AV and SA inhibition, bronchospasm Can induce arrhythmias