Agents Affecting the Renin-Angiotensin Pathway and Antihyperlipidemic Drugs PDF

# Agents Affecting the Renin-Angiotensin Pathway and Antihyperlipidemic Drugs ## The Renin-Angiotensin Pathway * The renin-angiotensin pathway is an important biochemical pathway for maintaining cardiovascular homeostasis including blood volume, arterial blood pressure, and electrolyte balance. *...

# Agents Affecting the Renin-Angiotensin Pathway and Antihyperlipidemic Drugs ## The Renin-Angiotensin Pathway * The renin-angiotensin pathway is an important biochemical pathway for maintaining cardiovascular homeostasis including blood volume, arterial blood pressure, and electrolyte balance. * Overproduction of renin and especially angiotensin II can result in hypertension and/or heart failure. ### Diagram of the pathway: The diagram shows the Renin-Angiotensin Pathway. The pathway starts with decreased blood pressure detected by the kidneys which results in the increased renin secretion. Renin from the kidneys converts angiotensinogen from the liver to Angiotensin I. Angiotensin-converting enzyme in the lungs converts angiotensin I to angiotensin II. Angiotensin II increases blood pressure via vasoconstriction and stimulation of the adrenal cortex, leading to secretion of aldosterone. Aldosterone increases blood pressure through increased sodium reabsorption and decreased urine volume. * **1. Kidneys:** The kidneys detect decreased blood pressure, resulting in increased renin secretion. * **2. Liver:** Renin converts angiotensinogen, a protein secreted from the liver, to angiotensin I. * **3. Lungs:** Angiotensin-converting enzyme in the lungs converts angiotensin I to angiotensin II. * **4. Blood Vessels:** Angiotensin II is a potent vasoconstrictor, resulting in increased blood pressure. * **5. Adrenal Cortex:** Angiotensin II stimulates the adrenal cortex to secrete aldosterone. * **6. Kidneys:** Aldosterone acts on the kidneys to increase Na+ reabsorption. As a result, urine volume decreases, and blood volume increases, resulting in increased blood pressure. ## The Renin-Angiotensin Pathway * Since the renin-angiotensin (RAAS) pathway produces a large number of effects on the cardiovascular system, it stands to reason that compounds that can inhibit the effects of renin or ACE, as well as blocking the binding of angiotensin II to its receptors, would be important drugs for the treatment of hypertension and other cardiovascular diseases ## Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors) ### Groups: * **Sulfhydryl-containing** (CAPTOPRIL) * **Dicarboxylate-containing** (ENALAPRIL, LISINOPRIL) * **Phosphonate-containing** (FOSINOPRIL) ### Mechanism of Action * ACEIs block the conversion of angiotensin I to angiotensin II. * Since ACE is a relatively nonspecific dipeptidyl carboxypeptidase, ACEIs also inhibit the metabolism of bradykinin, which leads to a number of physiological effects: * Vasodilation potentiating the hypotensive action of the ACEIs. * Bronchoconstriction is manifested by a dry cough. * Increased prostaglandin synthesis contributing to vasodilation, vascular permeability, and the production of some types of pain and inflammation. ### Diagram Showing Mechanism of Action: * Diagram shows a red "X" across the conversion of angiotensin I to angiotensin II. ### Physicochemical and Pharmacokinetic Properties * All ACEIs are amphoteric except CAPTOPRIL and FOSINOPRIL which are acidic. * The second carboxylic acid in the dicarboxylate series is ionized in the active form but unionized when in the prodrug (ester) form. ### Clinical Applications * Hypertension and heart failure. * Left ventricular dysfunction post myocardial infarction (MI) (captopril, enalapril, trandolapril). * Slows the progression of diabetic nephropathy and are therefore recommended to be used in hypertensive patients with diabetes. ### Adverse Effects * Hypotension, hyperkalemia (due to inhibition of aldosterone release). * Dry cough, rash (captopril). * Taste disturbances (captopril). * Headache. * Dizziness. * Fatigue. * Nausea. * Vomiting. * Diarrhea. * Acute renal failure. * Neutropenia. * Proteinuria. * Angioedema. ## Angiotensin II Receptor Blockers (ARBs) * Angiotensin II produces its biological effects by interacting with two receptor subtypes - Angiotensin 1 and Angiotensin 2. * **AT1 receptors** are located in brain, neuronal, vascular, renal, hepatic, adrenal, and myocardial tissues. * **AT2 receptors** are found in the brain, CNS, and myocardial and renal tissue. ### Diagram of the various drugs in this category: The diagram shows a variety of drugs in this category. The drugs all share a similar structure and have different substitutions at key locations. **Drug Name** | **Key Substitutions** -------|------ Losartan | Trp 842.60 Eprosartan | Ile 2887.39 Candesartan | Lys 1995.42 Valsartan | Azilsartan| Irbesartan | Telmisartan | Tyr 92ECL1 and Lys 1995.42 Olmesartan | ZD7155| Arg167ECL2 ### Mechanism of Action * Angiotensin II Receptor Blockers are AT1-receptor antagonists. They block the activation of angiotensin II type 1 (AT1) receptors. * The blockage of AT1 receptors directly causes vasodilation, reduces the secretion of vasopressin (ADH), and reduces the production and secretion of aldosterone, among other actions. ### Diagram Showing Mechanism of Action: * Diagram shows a red "X" across the binding of angiotensin II to its receptor. ### Physicochemical and Pharmacokinetic Properties * All ARBs are acidic due to the tetrazole ring and carboxylate groups. * The tetrazole ring containing ARBs have greater binding than those without the tetrazole ring and are more lipophilic. * It can be taken with meals. * Once or twice a day dosing. * All are primarily eliminated via the fecal route (exception olmesartan). * None require dosing adjustment in renal impairment. * Losartan and telmisartan are the only two that require dose reductions in patients with impaired hepatic function. ### Clinical Applications * The ARBs are approved for treatment of hypertension either alone or in combination with ACEIs, diuretics, β-blockers, and calcium channel blockers. * Unlike ACEIs, they do not affect bradykinin-induced vasodilation and bronchoconstriction. * **Other indications for ARBs:** * Irbesartan and losartan are approved for treatment of nephropathy in type 2 diabetics. * Losartan is approved for stroke prevention in patients with left ventricular hypertrophy. * Candesartan and valsartan are approved for treatment of heart failure. * Telmisartan is approved to reduce the risk of MI and stroke. ### Adverse Effects * Headache, dizziness, fatigue, hypotension, hyperkalemia (due to inhibition of aldosterone release), dyspepsia, diarrhea, abdominal pain, upper respiratory tract infection, myalgia, back pain, pharyngitis, and rhinitis. * Notably absent are the dry cough and angioedema seen with ACEIs. ### Drug-Drug Interactions * **ARBs**: Hyperkalemia when co-administered with potassium salts, K-sparing diuretics or drospirenone. * **NSAIDs**: alter effect by inhibiting the vasodilatory prostaglandins. * **Telmisartan**: increases digoxin levels. * **Losartan**: and its active metabolite levels decreased by rifampin. ## Renin Inhibitors * Developed as peptide mimetics to the octapeptide sequence of angiotensinogen recognized by renin. * Currently, **Aliskiren** is the only renin inhibitor available in the market. * Aliskiren is based on an amino-amide nonpeptide template. ### Mechanism of Action * Aliskiren directly inhibits the formation of both angiotensin I and angiotensin II. * Renin hydrolysis of angiotensinogen is the rate-limiting step in this pathway and is regulated by hemodynamic, neurogenic, and humoral signals. * Unlike ACEIs and ARBs, Aliskiren does not cause a compensatory increase of renin in the plasma. ### Physicochemical and Pharmacokinetic Properties * Aliskiren is a basic compound and marketed as the hemi fumarate salt. * High fat meals decrease absorption. * Elimination is primarily via the hepatobiliary tract. * No dose adjustment necessary with renal or hepatic impairment, it should be avoided in patients with severe renal impairment. ### Clinical Application * Aliskiren is approved for the treatment of hypertension as either monotherapy or in combination with hydrochlorothiazide, amlodipine, or valsartan. ### Adverse Effects * Renin Inhibitors: Diarrhea, abdominal pain, dyspepsia, gastroesophageal reflux, and rash. ### Drug-Drug Interactions * **Hyperkalemia** when co-administered with potassium salts, K-sparing diuretics. Irbesartan decreases both plasma levels and efficacy. * Plasma levels increased when co-administered with potent P-glycoprotein inhibitors such as atorvastatin, cyclosporine, and ketoconazole. * Aliskiren decreases the maximum plasma concentration of furosemide. ## Antihyperlipidemics * **Dyslipidemia:** aberrations in the level of serum lipids and/or lipoproteins. Can lead to negative cardiovascular events, specifically, atherosclerosis and CHD. * **Hyperlipidemia:** elevation of serum cholesterol, cholesterol esters, triglycerides, and/or phospholipids. Increases risk of CHD. Hypertriglyceridemia increases risk of pancreatitis. * **Hyperlipoproteinemia:** elevation of the lipoproteins that transport lipids through the bloodstream. Involves elevated low-density lipoproteins (LDLs) or very low-density lipoproteins (VLDLs) and/or decreased high-density lipoproteins (HDLs). ### Therapeutic approaches to the treatment of hyperlipidemia and hyperlipoproteinemia include: * Inhibiting intestinal reabsorption of bile acids (BAS). * Inhibiting triglyceride biosynthesis and VLDL formation (niacin). * Inhibiting intestinal absorption of dietary cholesterol (ezetimibe). * Stimulating serum triglyceride cleavage and clearance (fibrates). * Inhibiting de novo cholesterol biosynthesis (HMGCoA reductase inhibitors). ## Cholesterol and Bile Salts * The rate-limiting step in cholesterol biosynthesis is the stereospecific conversion of 3-hydroxy-3-methylglutarylCoA to R (-) mevalonic acid. * The catalyzing enzyme is HMG-CoA reductase (HMGR). * Cholesterol is the synthetic starting point for corticosteroids, sex steroids, and bile acids. * The anionic conjugate base of a bile acid is called a bile salt. * Bile acids promote the intestinal absorption of lipids and fat-soluble vitamins. ## Classifications * **Bile Acid Sequestrants** * **Nicotinic Acid** * **Cholesterol Absorption Inhibitor** (Ezetimibe) * **Fibric Acid Derivatives** * **HMG-CoA Reductase Inhibitors** ## Bile Acid Sequestrants * Cholestyramine * Colestipol * Colesevelam ### Mechanism of Action * These are nonabsorbable anionic exchange resins that trade chloride anions bound to strongly cationic centers for intestinal bile salts glycocholate and taurocholate. * Bile salts have higher affinity for the resin's cationic amines than chloride anion. * Bile salts are held to (sequestered by) the resin through strong ion-ion bonds. * Bound bile acids are excreted in the feces rat ### Clinical Applications * Taken once or twice daily. * Used as cotreatment with niacin or statins requires careful attention to administration timing. * The statin in BAS-statin co-therapy blocks the cholesterol biosynthesis surge induced by the fecal loss of bile acids. * Therapeutic benefit within 1 week (decreased LDL) to 1 month (decreased cholesterol). - Topical treatment in diaper rash. ### Adverse Effects * Bloating. * Abdominal discomfort. * Potentially severe constipation or bowel obstruction. * Aggravation of pre-existing hemorrhoids. * Gallstones (cholelithiasis). * Pancreatitis. * Hypoprothrombinemia and bleeding. ## Nicotinic Acid ### Mechanism of Action * Stimulates the receptor found in adipocytes, spleen, and macrophage. * Lowers serum triglycerides by inhibiting DAGAT2. * Inhibits receptor-mediated uptake of HDL, resulting in increased serum HDL. ### Structure Activity Relationship * Niacin must be anionic to be an effective antihyperlipidemic. * The carboxylic acid is essential. Nonionizable amides (e.g., nicotinamide) are inactive. * Essentially, any change made on the niacin structure results in inactivation. ### Clinical Applications * When used as an antihyperlipidemic, niacin is dosed up to 6 g/day. * Niacin administered as vitamin B3 is dosed at 13 to 20 mg/day. * Niacin induces cutaneous vasodilation when given in multigram doses. * GPR109A stimulation activates phospholipase A2. * Prostaglandin D2 (PGD2) is responsible for adverse effects. * Combating vasodilation include pretreatment with OTC (NSAIDs). * NSAIDs inhibit cyclooxygenase. * Other tactics to minimize vasodilation-related adverse effects should be in bedtime administration. ### Adverse Effects * Cutaneous vasodilation leading to flushing, itching, and headache. * Less common with extended-release formulations. * Gastrointestinal disturbances (nausea, diarrhea, flatulence). Taking with non-spicy foods or cold beverages can decrease GI distress. * Hepatotoxicity (high dose) ## Cholesterol Absorption Inhibitor (Ezetimibe) ### Mechanism of Action * Ezetimibe selectively blocks a cholesterol-active transporting protein at the intestinal brush border. * Inhibition of dietary cholesterol absorption increases serum LDL clearance and decreases total serum cholesterol. * A cholesterol biosynthesis surge occurs, but the net result is a decrease in serum LDL. ### Structure Activity Relationship * The 1,4-diaryl-β-lactam structure is important to activity. * Phenolic and alcoholic hydroxyls keep ezetimibe localized in the small intestine. * p-Fluoro groups block intestinal CYP-mediated aromatic hydroxylation, prolonging duration of action. ### Physicochemical and Pharmacokinetic Properties * Oral absorption is rapid and food independent. * Approximately 60% of an administered dose is absorbed. ### Clinical Applications * Marketed alone and in combination with the statin prodrug simvastatin and generally well tolerated, although it is not advised for use in patients with moderate to severe hepatic dysfunction. ## Fibric Acid Derivative ### AKA Phenoxyisobutyric Acids or Fibrates: * Gemfibrozil (Lopid) * Fenofibrate (Tricor and others) ### Mechanism of Action * Fibrates activate peroxisome proliferator-activated receptor alpha (PPARα), a hepatic nuclear protein that regulates genes controlling fatty acid metabolism. * PPARα stimulation enhances lipoprotein lipase expression. * This results in: * Triglyceride cleavage from VLDL, which facilitates receptor-mediated clearance. * FFA oxidation. * Inhibition of triglyceride synthesis. * Fibrates decrease serum triglyceride and VLDL levels. HDL levels increase. * Fibrates facilitate cholesterol removal from liver. ### Structure Activity Relationship * The pharmacophore for fibrate antihyperlipidemics is phenoxyisobutyric acid. * Esters must hydrolyze to release the active anion. * PPARα is flexible. A spacer of up to three carbons between isobutyrate and aryloxy groups is permitted. ### Physicochemical and Pharmacokinetic Properties * Despite the lack of a hydrocarbon spacer, fenofibrate has a higher log P than gemfibrozil due to: * The carbon-rich nonionizable isopropylcarboxylate ester. * The second phenyl ring and its p-chloro substituent. * Gemfibrozil must be given with meals. * Absorption efficiency is increased if administered with meals. * Fibrates are excreted predominantly by the kidney. ### Clinical Application * Well tolerated and effective in lowering serum triglyceride and VLDL levels. * Ineffective in treating Fredrickson's type I hypertriglyceridemia (elevated chylomicron levels). * It can be used in combination with other antihyperlipidemic in complex dyslipidemias. * Fibrates can sometimes induce liver function test abnormalities. * Fibrates are contraindicated (gemfibrozil) or used with caution (fenofibrate) in severe renal dysfunction. * Fenofibrate, but not gemfibrozil, is generally well tolerated in patients with mild to moderate impairment. ## HMG-CoA Reductase Inhibitors ### Mechanism of Action * Statins are competitive inhibitors of HMGR, the rate-limiting enzyme in cholesterol biosynthesis. * Statins successfully compete with the endogenous 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) substrate for access to the HMGR active site. * LDL reuptake receptor expression is augmented, leading to increased LDL clearance. * The two most potent statins (rosuvastatin, atorvastatin) also lower serum triglycerides. ### Structure Activity Relationship * Statins must be anionic to anchor to HMGR Lys 735. The dihydroxyheptan(en)oic acid segment is essential. * Hydroxyls at chiral C3 and C5 have important interactions at HMGR and must have the proper absolute configuration. (C3 requires the R configuration, Optimal configuration at C5 depends on C6-C7 saturation status. Dihydroxyheptanoic acid statins have 5R stereochemistry and dihydroxyheptenoic acids have the 5S configuration) * The ring component of statins is of two general types: * Naturally occurring statins have a 2',6'-dimethylhexahydronaphthylene ring system substituted with a methylbutyrate ester at C8'. * Addition of an a-CH3 to the methylbutyrate group (lovastatin vs. simvastatin) increases activity two-fold. * Synthetic statins have heteroaromatic ring systems. Isopropyl (or cyclopropyl) and pfluorophenyl substituents contribute to receptor affinity. ### Physicochemical and Pharmacokinetic Properties: **Lipophilic:** * Fluvastatin * Pitavastatin * Atorvastatin * Lovastatin * Simvastatin **Hydrophilic:** * Pravastatin * Rosuvastatin * **Lipophilic:** Carbon-rich ring, absorbed across GI, hepatic, and muscle cell membranes primarily by passive diffusion. * **Hydrophilic:** Carbon-poor, polar, actively transported across hepatic membranes predominantly by OATP1B1 ### Clinical Applications * Unexplained muscle tenderness should be reported to the pharmacist and/or physician. * Statins with short half-lives (fluvastatin, lovastatin, simvastatin) must be taken at bedtime to be active at early morning peak cholesterol biosynthesis times. * Statins with active metabolites (atorvastatin) or which are resistant to CYP-mediated inactivation (rosuvastatin, pitavastatin, pravastatin) can be taken at any time of day. * **Lovastatin** is taken with food. All other statins are food independent. * **Fluvastatin** serum levels increase dramatically if alcohol is consumed within 2 hours of dosing. * **Pravastatin** bioavailability increases in the presence of antacids, H2 antagonists, or proton pump inhibitors. * **Rosuvastatin** bioavailability decreases in the presence of antacids.