Anti Hypertensive Drugs PDF

ANTI-HYPERTENSIVE AGENTS Professor: Dr. Jennifer T. Co, MD, FPOGS, FPIDSOG Integrated Pharmacotherapeutics HYPERTENSION...

ANTI-HYPERTENSIVE AGENTS Professor: Dr. Jennifer T. Co, MD, FPOGS, FPIDSOG Integrated Pharmacotherapeutics HYPERTENSION BLOOD PRESSURE Overview Formula  In hypertensive patients, BP control systems are “set” at a higher level of blood pressure  HYPERTENSIVE CRISIS – systolic reading of 180 mmHg or higher or a diastolic reading of 110 mmHg or higher  HYPERTENSIVE URGENCY – SBP ≥ 180 or DBP ≥ 110 BUT no associated organ damage  HYPERTENSIVE EMERGENCY – generally occur at blood pressure levels exceeding 180 systolic or 120 diastolic, but can occur at even lower levels in patients whose blood pressure had not been previously high  Consequence – end-organ damage - Stroke - Loss of consciousness - Memory loss Stroke Volume - MI - Renal and eye damage  Preload - Aortic dissection o Filling volume of the heart - Unstable angina  Afterload - Pulmonary edema o Resistance the ventricles face on ejection - Eclampsia of blood o Tension the ventricle develops during ESSENTIAL OR PRIMARY HYPERTENSION contraction  Contractility  Patients in whom no specific cause of o Efficiency and vigor of contraction of the hypertension can be found heart muscle SECONDARY HYPERTENSION DETERMINANTS  Patients with specific etiology  LV preload or LV end diastolic pressure o Blood volume and pulmonary vein pressures, along with venous tone and ETIOLOGY rate of return  Contractility A. Increased cardiac output o Amount of cystolic Ca++ during the 1. Hypervolemia excitation sequence (major), condition of i. Renal artery stenosis cardiac muscle ii. Renal disease  LV afterload or LV end systolic pressure iii. Hyperaldosteronism o Aortic pressure, peripheral vascular iv. Hypersecretion of ADH resistance (arterioles) v. Aortic Coarctation vi. Pregnancy Induced HPN (PIH) Regulation of Blood Pressure 2. Stress – sympathetic activation 3. Pheochromocytoma – increased 4 PRIMARY PHYSIOLOGIC SITES OF BP CONTROL catecholamines B. Increased vascular resistance 1. Stress – sympathetic activation  Autonomic nervous system 2. Atherosclerosis  Heart 3. Renal artery disease – increased  Vasculature angiotensin II  Kidneys 4. Pheochromocytoma – increased catecholamines C. Thyroid dysfunction D. Diabetes E. Cerebral ischemia Page 1 of 12 4 SITES OF REGULATION OF CO AND PVR DRUGS THAT ALTER SODIUM AND WATER BALANCE (DIURETICS)  Postcapillary venules (capacitance vessels)  Arterioles  Heart  Kidneys Thiazides  Hydrochlorothiazide, Chlorothiazide, Bendroflumethiazide, Hydroflumethiazide,  Regulation of blood pressure in hypertensive Methylclothiazide, Polythiazide, patients differs from healthy patients in that the Trichlomethoazide baroreceptors and the renal blood volume o Inhibit Na/Cl transporter predominantly in pressure control systems appear to be set up at a the distal convoluted tubule higher level of blood pressure. Loop Diuretics SHORT-TERM REGULATION OF BP: POSTURAL BARORECEPTOR  Furosemide, Bumetanide, Torasemide, Ethacrynic REFLEX acid o Inhibit NaCl reabsorption in the thick Rapid, moment to moment adjustment in BP → reduce ascending loop of Henle (Na+/K+/2Cl- afferent signals to the CNS → reduce vagal tone → transporter) increase sympathetic tone → regulation of BP Potassium Sparing Diuretics  Spironolactone, Eplerenone, Triamterene, Amiloride LONG-TERM REGULATION OF BP: RENAL BLOOD VOLUME- o Prevent K secretion by antagonizing the PRESSURE CONTROL SYSTEMS effect of aldosterone in the collecting tubules  Reduction in renal perfusion pressure leads to  Triamterene and amiloride intrarenal redistribution of blood flow and o inhibit Na+ influx through ion channels increased reabsorption of salt and water (Na/K transporters) in the luminal  Decreased pressure in renal arterioles as well as membrane sympathetic neural activity (via adrenoceptors)  Spironolactone, eplerenone stimulates production of renin o direct pharmacologic antagonism of  Renin increases production of angiotensin II mineralocorticoids receptors  Angiotensin II causes:  Limited natriuretic activity o Direct constriction of resistance vessels o Stimulation of aldosterone synthesis in the Sulfonamide adrenal cortex, which increases renal  NOT a thiazide but qualitatively similar to thiazide sodium absorption and intravascular  Indapamide, Metolazone, Xipamide, blood volume Chlorthalidone, Quinethazone BASIC PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS MOA AND HEMODYNAMIC EFFECTS Primarily be depleting body sodium stores  Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possible related to altered sodium- calcium exchange with a resultant increase in intracellular calcium  These effects are reversed by diuretics  Initially: Increase Na+ excretion → decrease blood volume → decrease in cardiac output  After 6-8 weeks: CO return to normal and PVR declines Page 2 of 12  Effect on vascular resistance (vessel stiffness and ADVERSE EFFECTS neural reactivity) o Decrease Na+ of vessel walls → decrease Na+Ca2+ exchange → decrease intracellular Ca2+ concentration THERAPEUTIC USE  Effectively lower the BP by 10-15 mmHg in most patients  As monotherapy (mild to moderate hypertension) or in combination with other drugs Thiazide diuretics  Hypokalemia (except for K-sparing diuretics)  Appropriate for patients with mild or moderate  Hypomagnesemia, impaired glucose tolerance hypertension and normal renal and cardiac  Hyperlipidemia, reduced uric acid excretion function  K-sparing diuretics + ACE inhibitors or renal  Chlorthalidone is likely to be more effective than insufficiency = HYPERkalemia hydrochlorothiazide because it has a longer  Diuretics + digitalis, anti-arrhythmia, those with MI duration of action or LV dysfunction = HYPOkalemia (hazardous)  Hypertension, congestive heart failure, nephrolithiasis secondary to idiopathic hypercalciuria, nephrogenic diabetes insipidus, SUMMARY OF THE MOA AND EFFECTS OF VARIOUS CLASSES severe resistant edema OF DIURETICS Loop Diuretics (Furosemide)  More powerful diuretics (e.g. those acting on the loop of Henle)  Necessary is severe hypertension, when multiple drugs with sodium-retaining properties are used  In renal insufficiency, when glomerular filtration rate is less than 30 40 mL/min  In cardiac failure or cirrhosis, in which sodium retention is marked  Hyperkalemia – enhanced by simultaneous NaCl DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM and water administration  Salt and water retention – acute pulmonary Centrally Acting Sympathoplegic Drugs edema, chronic heart failure, hepatic cirrhosis with ascites  Methyldopa  Acute renal failure and hypercalcemia  Clonidine  Anion overdose – bromide, fluoride, iodide  Guanfacine o Saline solution administered to replace  Guanbenz urinary loss of Na and Cl to avoid ECV depletion MOA:  Reduce sympathetic outflow from vasopressor Potassium-sparing diuretics centers in brainstem and retain or with increased  Useful both to avoid excessive potassium sensitivity to baroreceptor control depletion and to enhance the natriuretic effects of other diuretics  Congestive heart failure, aldosteronism and hyperaldosteronism, lithium-induced diabetes insipidus Aldosterone receptor antagonists  Favorable effect on cardiac function in people with heart failure Page 3 of 12   Mechanism and site of action o Gradual depletion of NE in the nerve ending (peripheral) o Neuronal uptake is necessary for the hypotensive activity of the drug  Main Effects: o Decrease in PVR and HR → decrease BP  Drug Interaction: o Drugs that block catecholamine uptake or displaces amines from nerve terminals, cocaine, amphetamines, TCA, phenothiazines, phenoxybenzamines  Adverse Effects: o Can produce all of the toxicities expected from pharmacologic sympathectomy including marked postural hypotension, diarrhea, and impaired ejaculation  Pharmacokinetic: o Poorly absorbed from the GI o Onset slow, peak of action 1-2 weeks o Metabolites excreted in urine o Half-life: 5 days  Use: Not used anymore because of severe side effects THERAPEUTIC USE: Reserpine  Treatment of hypertension, either alone or with  Disrupts norepinephrine vesicular storage other agents  Mechanism and site of action  Usually used after other agents have failed due to o Interferes with vesicular membrane side effects associated transporter (VMAT) →  Also may be used for treatment of severe depletes NT (NE, dopamine, serotonin) in dysmenorrhea, menopausal flushing, glaucoma the storage vesicle of the central and  Clonidine is useful in the management of peripheral nerve endings withdrawal symptoms in opioid- or nicotine- o Reserpine effects on adrenergic vesicles dependent persons are irreversible and occurs throughout the body Ganglionic Blocking Agents  Main effects o Depress CNS function centrally and  Trimethaphan peripherally decrease HR, contractility  Mecamylamine (CO) and peripheral vascular resistance  Adverse effects MOA: o Depression, sedation, nightmares, ulcers,  Competitively block nicotinic cholinoceptors on diarrhea, abdominal cramping, nasal postganglionic neurons in both sympathetic and stuffiness, orthostatic hypotension, dry parasympathetic ganglia mouth, impotence and extrapyramidal effects ADVERSE EFFECTS:  Sympathoplegia Alpha Adrenoreceptor Antagonist o Excessive orthostatic hypotension and sexual dysfunction  Prazosin  Parasympathoplegia  Doxazosin o Constipation, urinary retention,  Terazosin precipitation of glaucoma, blurred vision, dry mouth, etc. Main Effects  Decrease PVR → decrease BP Adrenergic Neuron-Blocking Agents Pharmacokinetics  Terazosin – extensively metabolized but undergoes very little first-pass metabolism with a Guanethidine half-life of 12 hours  Prevents norepinephrine release from nerve  Doxazosin has an intermediate bioavailability and terminals a half-life of 22 hours  Prazosin - half-life is 22 hours Page 4 of 12 Adverse Effects o Some patients may experience  1st dose phenomenon which is common in withdrawal symptoms (due to patients who are salt- and volume-depleted, fluid upregulation or super sensitivity of B- retention, dizziness, headache, palpitations adrenoceptor, thus the drug should not  Long term treatment causes little postural be withdrawn abruptly) hypotension, a precipitous drop in standing blood Metoprolol and Atenolol pressure develops in some patients shortly after  Relative cardioselectivity is advantageous in the first dose is absorbed. Therefore, first dose treating hypertensive patients who also suffer from should be small and should be administered at asthma, diabetes, or peripheral vascular disease bedtime  Approximately equipotent to propranolol in  Some patients develop a positive test for inhibiting stimulation of B1 adrenoceptors such as antinuclear factor in serum while on prazosin those in the heart but 50- to 100-fold less potent therapy, but this has not been associated with than propranolol in blocking 2 receptors rheumatic symptoms  Metoprolol is extensively metabolized by CYP2D6 with high first pass metabolism. The drug has a Clinical Use relatively short half-life of 4 to 6 hours, but the  More effective when used in combination with B extended-release preparation can be dosed blocker and a diuretic, than when used alone daily.  Used primarily in men with concurrent  Atenolol is not extensively metabolized hypertension and benign prostatic hyperplasia  Excreted primarily in the urine  Half-life of 6 hours; usually dosed once daily Tamsulosin  Atenolol is reported to be less effective than  Competitive α1 antagonist with a structure quite metoprolol in preventing the complications of different from that of most other α1-receptor hypertension blockers Nadolol, Carteolol, Betaxelol and Bisoprolol  High bioavailability and a half-life of 9 to 15 hours  Non-selective B-receptor antagonist  Metabolized extensively in the liver  Betaxolol and bisoprolol are B1-selective blockers  Higher affinity for α1A and α1D receptors than for that are primarily metabolized in the liver but have the α1B subtype long half lives  Relatively greater potency in inhibiting  Because of long half lives these drugs are contraction in prostate smooth muscle versus commonly administered on once OD vascular smooth muscle compared with other a-1  Increases in dosage to obtain a satisfactory selective antagonists therapeutic effect should take place no more than every 4 or 5 days Beta Adrenergic Blocking Agents  Dose adjustment in Nadolol and Carteolol among patients with reduced renal function Pindolol, Acebutolol, Penbutolol  Partial agonists, i.e., B blockers with some intrinsic sympathomimetic activity  Lower blood pressure but are rarely used in hypertension  Beneficial for patients with bradyarrhythmia or peripheral vascular disease  In severe hypertension, all beta blockers are useful in preventing the reflex tachycardia that often Labetalol, Carvedilol, Nebivolol – both beta blocking and results from treatment of direct vasodilators vasodilating effects  Reduce mortality after MI and some also reduce Labetalol mortality in patients with heart failure  Has 3:1 ratio of beta:alpha antagonism after oral dosing Propranolol  Blood pressure is lowered by reduction of systemic  Mechanism and Sites of Action vascular resistance (via blockade) without o Decreases blood pressure primarily as a significant alteration in heart rate or cardiac result of a decrease in cardiac output output o Inhibits the stimulation of renin production  Useful in treating the hypertension of by catecholamines (mediated receptor) pheochromocytoma and hypertensive o Propranolol’s effect is due in part to emergencies depression of the RAAS  Pharmacokinetics Carvedilol o Resting bradycardia and a reduction the  S (-) isomer is a non-selective B adrenoreceptor, heart rate during exercise but both S (-) and R (+) have approximately equal  Adverse Effects and Toxicity α-blocking potency o Result primarily from cardiac vascular or  Useful in patients with both heart failure and bronchial beta receptors activity hypertension Page 5 of 12 Nebivolol  Adverse effects  Highly selective B1 blocking effects thus its effect o Reflex tachycardia, headache, flushing, is not mediated by α blockade increase intraocular pressure  Vasodilating effect may be due to an increase in  Clinical uses endothelial release of NO via induction of o Hypertensive emergencies, endothelial nitric oxide synthase postoperative hypertension Esmolol Hydralazine  Rapidly metabolized via hydrolysis by RBC  Mechanism of action esterases o Interferes with IP3 on Ca+2 release from  Has a short half life of 9 minutes and is sarcoplasmic reticulum administered by IV route  Site of action – arterioles but not veins  Used for management of intraoperative and  Clinical use postoperative hypertension, and sometimes for o Severe hypertension, hypertension in hypertensive emergencies, particularly when pregnancy hypertension is associated with tachycardia  Pharmacokinetics o Absorption: Well absorbed orally Proposed Mechanisms: (Propranolol and other beta o Distribution: 25% bioavailability blockers) o Metabolism: Liver (Acetylation) 1. Block cardiac B1 receptors → lower CO  Rapid acetylators have greater 2. Block renal B1 receptors → lower renin → lower first pass metabolism, lower blood angiotensin II → lower PVR levels, and less antihypertensive 3. Decrease sympathetic vasoconstrictor nerve benefit from a given dose than activity do slow acetylators  For slow acetylators 400 mg/day Vasodilators (10-20% incidence) LE syndrome may develop A. Calcium antagonist  T ½ = 1.5 – 3 H B. Drugs that activate potassium channels  Adverse effect C. Drugs that act via cyclic nucleotides o Headache, nausea, anorexia D. Cyclase activation cGMP o Sympathetic stimulation: palpitations, E. Indirectly acting vasodilator drugs reflex tachycardia, angina, ischemic arrhythmia  All the vasodilators that are useful in hypertension o Lupus erythematosus like syndrome relax the muscle of arterioles (decrease in PVR) (arthralgia, myalgia, skin rashes, and  Decreased arterial resistance and decreased fever) mean arterial pressure elicit compensatory o Peripheral neuropathy and drug fever responses  These responses are mediated by baroreceptor, DRUGS THAT ACTIVATE THE POTASSIUM CHANNEL SNS and renin, angiotensin, and aldosterone  Minoxidil  Diazoxide  Cromikalim  Lemakalim  Nicorandil Minoxidil  Mechanism of action o Opening of potassium channel by minoxidil sulphate (active metabolite) → K efflux → hyperpolarization → DIRECT ACTING VASODILATORS vasodilatation  Site of action – arterioles but not vein Fenoldopam  Pharmacokinetics  Mechanism of action o Absorption: Well absorbed from GIT, o D1 – dopamine receptor agonist Bioavailability of 90% o Site of action: peripheral arteries o Distribution: action may persist for 24H  Pharmacokinetics o Metabolism: Liver (Conjugation) o Metabolism: liver (conjugation)  T ½ = 4 hours o T ½ = 10 mins  Adverse Effects o Administered by continuous infusion and o Sympathetic stimulation: Tachycardia / initiated at low doses palpitations, angina, edema, headache, sweating, hypertrichosis Page 6 of 12 Diaxozide o Thiocyanate toxicity maybe manifested  Mechanism of Action as weakness, disorientation, psychosis, o Bind to SUR1 subunit of K+/ATP channels in muscle spasm, and convulsion. This is pancreatic B cells → stabilizes ATP-bound confirmed by serum concentration (open) state → B cells hyperpolarized → greater than 10 mg/dL inhibit insulin secretion o Methemoglobinemia maybe observed  Site of Action: arteriole  Antidote:  Pharmacologic actions o Sodium thiosulfate as sulfur donor o Rapid fall in ABP, increase in cardiac o Hydroxocobalamin combined with output cyanide to form non-toxic o Similar chemically with thiazide but has no cyanocobalamin diuretic activity  Pharmacokinetics CALCIUM CHANNEL ANTAGONISTS/BLOCKERS o Distribution: Bound extensively to serum albumin and vascular tissue o Onset of action: 5 minutes o Duration of action: 4-12 hours o Metabolism: Not well characterized T ½ = 24 hours, unchanged Excretion: unchanged  Adverse effects o Excessive hypotension, reflex sympathetic response → angina → ischemia → cardiac failure o Hyperglycemia, cardiac failure  Clinical uses o Hypertensive emergencies o Treatment of hypoglycemia secondary to insulinoma  Drug interaction o Hypotensive activity is greater if pretreated with B-blockers DRUGS THAT ACT VIA CYCLIC NUCLEOTIDES CYCLASE ACTIVATION CGMP  Mechanism of Action (in hypertension and in part Nitroprusside (Nitropress) in angina)  Mechanism of action o Inhibition of calcium influx into arterial o Activates guanylyl cyclase either via smooth muscle release of nitric oxide or by direct  Pharmacokinetics stimulation of the enzyme → increase o Hemodynamic differences may influence cGMP → relaxes vascular smooth muscle the choice of particular agent  Sites of action: arteries and veins o Nifedipine and other DHP agents are  Pharmacological actions: more selective as vasodilators and have o Reduces the peripheral vascular less cardiac depressant effect than resistance and venous return verapamil and diltiazem o No change or slight decrease in CO o Reflex sympathetic activation with slight  Pharmacokinetics tachycardia maintains or increase o Metabolism: rapidly metabolized within cardiac output in DHP RBC → liberating cyanide which is o Verapamil has the greatest depressant metabolized by rhodanese in the effect on the heart and may decrease HR presence of sulfur donor → Thiocyanate and CO (less toxic) → distributed then in ECF and o DHP sustained release (SR) or those with eliminated longer half-lives provide smoother blood o Excretion: Kidneys pressure control than short acting oral o Duration of action: 1 to 10 minutes DHP. These are the preferred drugs in  Clinical uses: hypertensive emergencies, severe chronic hypertension heart failure  Clinical Use  Adverse effects: (due to accumulation of o Emergency management of severe cyanide) hypertension, safe in pregnancy o Metabolic acidosis, arrhythmias, excessive hypotension, death Page 7 of 12   Adverse Effects o Severe hypotension o Acute renal failure especially among patients with bilateral renal stenosis o Hyperkalemia, dry cough with wheezing and angioedema o Minor reactions: altered sense of taste, allergic skin rashes and drug fever  Contraindications o Pregnancy INDIRECTLY ACTING VASODILATORS o Renal insufficiency  Drug interaction 1. Inhibit vasoconstriction Clonidine, Methydopa o Potassium supplement or potassium 2. Renin-angiotensin sparing system o NSAIDs Drugs that block renin Propranolol secretion Angiotensin Receptor Blockers (ARBs) Renin inhibitors Aliskiren  Mechanism ACE Inhibitors Sulfhydryl 2containing: o NO effect on bradykinin Captopril, Fentiapril, o More selective blocker of angiotensin Pivalopril, Zofenopril, and more complete inhibition of Alacepril angiotensin action compared to ACEI  Adverse effect Dicarboxyl 2containing: o Cough and angioedema are uncommon Enalapril, Lisonopril, o Similar to ACE inhibitors including the Benazepril, Quinapril, hazard of use during pregnancy Moexipril, Ramipril,  More commonly used among patients who have Spirapril, Perindopril, had adverse effects to ACEI Pentopril, Cilazapril DIURETICS Phosphorous containing: Fosinopril  Act by reduction of blood volume and direct Angiotensin II Candesartan, Irbesartan,  vascular effects Receptor Blockers Telmisartan, Valsartan,  Deplete body sodium stores Losartan, Olmesartan  Often provide adequate treatment for mild to moderate hypertension ACE Inhibitors  In more severe hypertension combined with  Mechanism of Action sympathoplegic and vasodilators o Inhibits peptidyl dipeptidase and inactivates bradykinin o Hypotensive action results from both inhibitory action on RAAS and stimulatory action Kallikrein-Kinin system  Enalapril is a product that is converted by hydrolysis to an enalaprilat, a converting enzyme inhibitor  Enalaprilat in itself is primarily use for hypertensive emergencies and given thru IV  Main effects o Decreased PVR, decreased BP o Cardiac output and heart rate are not significantly changed o These agents do not result in reflex sympathetic activation o There is no correlation between plasma renin activity and hypotensive effects of the drug  Clinical Use o Recommended among diabetics o Patients with chronic kidney disease o Heart failure and MI are proved to be responsive with these drugs Page 8 of 12  Classes of Diuretics CARBONIC ANHYDRASE INHIBITORS  Acetazolamide: used for glaucoma, altitude sickness, and to reduce metabolic alkalosis  Block carbonic anhydrase in the brush border and cytoplasm of proximal tubule cells and other tissues (eye and brain)  Orally active; some members of the group (dorzolamide) are available in topical form for glaucoma; duration of action: 8 — 12 hours  Toxicities: o Oral: GI upset, paresthesias, hepatic encephalopathy (if with severe hepatic impairment) o Cross-allergenicity with sulfonamides ANTIDIURETIC HORMONE AGONISTS Electrolyte Changes Produced by Diuretic Drugs  Vasopressin, desmopressin (analogue of vasopressin) o For pituitary deficiency diabetes insipidus o Collecting ducts are responsive to vasopressin and insert additional water channels (aquaporins) into the luminal membrane facilitate water resorption —> restores urine concentrating power to normal  NOT useful for nephrogenic diabetes insipidus o Does not respond to pituitary peptides; OSMOTIC DIURETICS treated INDIRECTLY with thiazides urine osmolality is increased but not to normal maximal levels  Mannitol: for acute glaucoma, increased ICP, o Thiazides decrease blood volume —> protects kidney from solute overload due to crush lead to compensatory water injury or chemotherapy reabsorption from proximal tubule —>  Small, non-absorbable molecule; osmotically reduces urine volume inhibits resorption of water in water-permeable  Duration of action portions of the nephron o Vasopressin and desmopressin 4 — 8 hrs  Given IV; duration of action: 1 —2 hours o Thiazides —> up to 12 hours  Toxicities: headache, GI upset, hypotension, mild  Toxicities hyponatremia, followed by hypernatremia o Vasopressin and desmopressin — rarely  REMEMBER: In HF, the increased hydrostatic cause vasoconstriction with hypertension pressure proximal to the left atrium causes or coronary spasm transudation in the lungs o Thiazides — hyponatremia, o Prior to diuresis, mannitol initially increases hyperlipidemia, hyperuricemia plasma volume due to its effects on  Demeclocycline — prevents hyponatremia in elevating plasma oncotic pressure SIADH; MOA unclear o Increased plasma volume -Y increased o Can cause iatrogenic diabetes insipidus left atrial preload in the face of (like lithium) by blocking ADH-like decompensation (even at a lower peptides preload) —> increased left atrial preload o Used orally; duration of action 10 — 16 hrs and PCWP —> exacerbation of fluid o Toxicities: transudation in the lungs  Like other tetracyclines —  Mannitol is confined to the extracellular disorders of developing bones compartment exclusively raises osmolarity of the and teeth in children; rash, GI ECF -Y draws water out of intracellular upset, hepatic dysfunction compartment -Y higher over all extracellular volume -Y volume overload and edema Page 9 of 12   Conivaptan  Chlorothiazide — less lipid soluble and given in o Antagonist at Via, V2 receptors large doses o Clinical applications: SIADH,  Chlorthalidone slowly absorbed, longer duration hyponatremia of action o PK: administered parenterally  Bendrofluazide, Hydrochlorothiazide, o Toxicities: infusion site reactions Cyclopenthiazide and Chlorothiazide — onset of  Tolvaptan action 12 hrs, maximum 4-6 hrs, duration 8-12 hrs o like conivaptan but more selective for V2  Indapamide — excreted primarily by the biliary receptors system  All secreted by organic secretory system and LOOP DIURETICS compete with secretion of UA by that system  CLINICAL USES  Furosemide, ethacrynic acid; used for conditions o Hypertension, associated with moderate or severe hypertension o Congestive heart failure, or fluid retention (heart failure, cirrhosis, nephrotic o Nephrolithiasis 2' to idiopathic syndrome) hypercalciuria,  Most efficacious diuretics currently available o Nephrogenic diabetes insipidus,  Block Na+/K+/2Cl- symporter in the ascending o Severe resistant edema limb of the loop of Henle  TOXICITIES: o Indirect effect: increase calcium and o hypokalemic metabolic alkalosis, magnesium excretion hyperuricemia, impaired carbohydrate o Useful in the management of severe tolerance, hyperlipidemia (5-15% hypercalcemia; must be given with saline increase in serum cholesterol and LDL), infusion to prevent hemoconcentration hyponatremia, hypercalcemia, allergic  Orally active but can also be used IV; duration of reactions, weakness, fatigability, and action: 2 —4 hours paresthesias, impotence has been  Toxicities: hypokalemia, hyperurecemia, reported probably related to volume hypomagnesemia, ototoxicity, renal impairment depletion o Effects are diminished by NSAIDs o All are sulfonamides EXCEPT ethacrynic acid POTASSIUM-SPARING (ALDOSTERONE ANTAGONIST) DIURETICS  Used to prevent potassium wasting by otherdiuretics  Spironolactone and eplerenone o Particularly effective in treating heart failure and other high aldosterone THIAZIDES conditions o Block cytoplasmic aldosterone receptor;  Prototype: Hydrochlorothiazide weak antagonism of androgen receptors  One of the first-line agents for hypertension o Eplerenone — more selective for  Inhibit Na/Cl transporter predominantly in the mineralocorticoid receptor distal convoluted tubule  Reduces blood/extracellular volume and cardiac  Amiloride and triamterene output initially o Block sodium channels in the  Eventually, normal cardiac output, I PVR (due to collecting tubule depleted sodium stores)  Orally active; duration of action is 12 — 72 hours  Toxicities: hyperkalemia (major), GI upset o Spironolactone — antiandrogen effects Page 10 of 12   In the general population