Pharmacology Notes (Chapter 20 and 21)

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CHAPTER 20 Pharmacology of Volume Regulation Aliskiren: Inhibits enzymatic activity of renin, blocks renin -> AT1 conversion Effective

ve anti-hypertensive that can be used in patients with Renal Insufficiency ACE Inhibitors Inhibit conversion of AT1 -> AT2, display 3 patterns of metabolism Can cause cough and angioedema (not breaking down bradykinin, which is a potent vasodilator) Also cause acute renal failure in patients with bilateral renal artery stenosis Used as first line defense in patients with left-ventricular wall dysfunction or diabetes Contraindicated in pregnancy Captopril: (First Pattern) Active when administered, prototypical ACE inhibitor nd Enalapril and Ramipril: (2 and most common pattern) Prodrug when administered, converted in plasma Lisinopril: (Third Pattern) Administered in the active form and excreted unchanged Losartan and Valsartan: AT1 receptor Antagonists - inhibit the action of AT2 at its receptor Allow more complete inhibition of AT2 actions b/c ACE is not the only enzyme that can make AT2 AT1 receptor antagonists can protect against stroke through beneficial secondary effects Have no effect on bradykinin, therefore limit incidence of angioedema and drug-induced cough Nesiritide: B-type natriuretic peptide (BNP), promotes water excretion due to a great degree of Na+ excretion Used for short term management of decompensated heart failure Can cause hypotension (esp. w/ ACE inhibitor) and is associated with increased risk of renal dysfunction Democycline: Tetracycline analogue used for the treatment of SIADH mechanism uncertain Conivaptan: Nonpeptide vasopressin receptor antagonist, requires IV infusion (v1 = VC, v2 = water reabsorption) Tolvaptan: Orally bioavailable, V2 receptor-selective, Can be used to treat renal cysts Terlipressin: Investigational vasopressin analog with moderate V1 agonist activity and specificity May reduce portal hypertension and improve renal hemodynamics in liver failure and ascites Acetazolamide: Carbonic Anhydrase Inhibitor, reversibly inhibits cytoplasmic and luminal carbonic anhydrase Leads to increased HCO3- delivery to distal nephron, which is excreted and leads to diuresis Mild-to-Moderate Metabolic Acidosis, d/t inhibition of H+ secretion in PT and intercalated cells Used to restore acid-base balance in heart failure patients treated with loop diuretics Can be used in the treatment of high altitude sickness, glaucoma and gout Topiramate: Carbonic anhydrase inhibitor used for the treatment of epilepsy Can produce mild-to-moderate acidosis d/t impaired renal acidification of urine Mannitol: Osmotic diuretics, small molecules filtered at the glomerulus, but not absorbed in the nephron st Effect is greatest at the PT (1 aid says Thin Descending), where most osmotic water resorption takes place Can be used acutely to treat increased intracranial pressure d/t trauma Loop Diuretics: Act at the TAL to reversibly and competitively inhibit NKCC2 in the luminal (apical) membrane Can lead to excretion of Ca2+ and Mg2+ Predisposes to metabolic acidosis and hypokalemia Associated with ototoxicity, d/t changes in electrolyte handling in the endolymph Furosemide/Bumetanide/Torsemide: Sulfonamide derivatives Ethacrynic Acid: Therapeutic option for patients allergic to sulfa drugs Hydrochlorothiazide: Thiazide diuretic that inhibits NaCl reabsorption in the DCT Unmasks diabetes in patients at risk for impaired glucose metabolism d/t decreases glucose tolerance Can not be administered with antiarrhythmic agents b/c it predisposes patients to torsades de pointes Chlorthalidone: Longer acting thiazide diuretic, that can be taken once per day Can prevent nocturnal BP elevation that correlates with end-organ damage Spironolactone and Eplerenone: inhibit biosynthesis of new Na+ channels (via Aldosterone) in principal cells K+ spare Thiazide diuretic @ Collecting Ducts, greater efficacy in obesity-associated hypertension Spironolactone can inhibit the androgen receptor and cause impotence and gynecomastia in men Amiloride and Triamterene: Competitive inhibitors of the ENaC Na+ Channel

Chapter 21 Pharmacology of Vascular Tone - (All agents discussed are vasodilators) NTG, Isosorbide dinitrate, or 5-mononitrate - chemically reduced to release NO that can dissolve in biological fluids Venous dilation predominates at therapeutic doses, increases venous capacity -> decrease in preload and O2 demand Coronary circulation, NTG dilates large epicardial arteries -> prevents development of CORONARY STEAL Dipyridamole associated with coronary steal phenomenon produce intense dilation of coronary resistance vessels NTG can cause hypotension -> reflex tachycardia -> decrease O2 supply and myocardial perfusion time Isosorbide mononitrate longer half-life, approx. 1 hour; Isosorbide 5-mononitrate prolonged effect, no first pass Removal of the patch at night can limit tolerance, called nitrate free intervals Important in the treatment of unstable angina (rest angina) stops coronary artery occlusion Contraindications: Patients w/ Hypotension, elevated intracranial pressure, HOC (decreased preload) Inhaled NO selectively dilates the pulmonary vasculature, little effect on systemic pressure d/t rapid inactivation Used to treat pulmonary hypertension in a newborn Sodium Nitroprusside liberates NO through non-enzymatic process, vasodilates both arteries and veins Used for HTN emergencies, severe cardiac failure, and Ergot alkaloid toxicity Must be used with continuous BP monitoring breaks down to thiocyanate in the liver -> excreted via kidneys Thiocyanate toxicity can occur with renal dysfunction > disorientation, psychosis, muscle spasms, and seizures Excessive accumulation can lead to acid-base disturbances, cardiac arrhythmias and even death Phosphodiesterase Inhibitors - prevent the hydrolysis of cAMP/cGMP into 5-AMP/GMP Amrinone and Milrinone selective for PDEI found in cardiac and smooth muscle Sildenafil used for PH - selective for PDE5 (smooth muscle of corpus cavernosum, retina, vascular) E.D. Vardenafil and Tadalafil (longer onset, prolong half-life) same mechanism as sildenafil Headache and flushing, can lead to refractory hypotension do NOT take w/ organic nitrates Associated w/ permanent vision loss called nonarteritic ischemic neuropathy Degraded via hepatic P450 3A4 theoretical risk stems from taking PDEI + anti-HTN VD + inhibitor of P450 3A4 Ca
2+

Channel Blockers inhibit Ca entry through the L-type channel reduce systemic vascular resistance, lowers BP 2+ 2+ Decreased Ca entry -> low intracellular calcium -> reduced Ca -CAM activation of MLCK reduced contraction Works on vascular smooth muscle and myocardium, predominantly arterial vasodilators Used in the treatment of HTN, cardiac arrhythmias, and some forms of angina 2+ Skeletal muscle not effected d/t the fact that it depends on intracellular pools of Ca Verapamil and diltiazem = bradycardia, AV block, and heart failure, in excess NO !-blockers @ same time

2+

1. Dihydropyridines - This class causes more arterial vasodilation, little effect on cardiac, binds to the N binding site 2+ This class does NOT alter the recovery of the Ca channel does NOT slow cardiac conduction velocity Nifedipine (synergistic effect w/ diltiazem) excreted via the kidney, rapid onset, can cause reflex tachycardia rd Amlodipine (3 generation) high bioavailability, effective at lower dosages, causes less reflex tachycardia Clevidipine only available in IV form, administered for HTN and emergency 2+ 2. Benzothiazepines - Binds to the D site region of the Ca channel Diltiazem slows cardiac conduction via influx/recovery of calcium channel, excreted via liver 2+ 3. Phenylalkylamines - Binds to the V site/region of the Ca channel Verapamil greater suppressive effect on cardiac contractility than Diltiazem K+ Channel Openers cause direct arterial vasodilation by opening ATP-modulated K+ channels hyperpolarizes the cell 2+ 2+ Class of drugs basically stops the opening of the Ca channels no influx of Ca - no smooth muscle contraction Act on smooth muscle cells -> decrease arterial blood pressure, adverse effects include headache and flusing When used as monotherapy, can cause sympathetic discharge -> tachycardia and increased cardiac work Use of !-blockers in combo w/ arterial vasodilators can block effects of reflex sympathetic activity CONTRAINDICATED IN PHEOCHROMOCYTOMA Endothelin Receptor Antagonists both used for PULMONARY HTN Bosentan competitive antagonist @ ETA/B used for pulmonary HTN, increases AST, monitor liver function Ambrisentan competitive antagonist @ ETA used for pulmonary HTN, less hepatotoxicity than Bosentan Hydralazine oral administered, used for HTN and heart failure (w/ nitrate - prevents tolerance, can cause lupus-like syndrome !1 Adrenergic Antagonists block the G protein coupled receptor that associates with Gq -> phospholipase C Prazosin effect greater in arterioles than venules, cause reduction in arterial pressure, treat HTN Terazosin no effect on vascular smooth muscle, instead used for prostatic smooth muscle

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