PBS 3107 Cardiovascular-Renal Drugs Antihypertensive Agents PDF

PBS 3107 Cardiovascular-Renal Drugs Antihypertensive Agents BASIC PHARMACOLOGY OF ANTIHYPERTENSIVE HYPERTENSION AGENTS - Systolic blood pressure of 140 or greate...

PBS 3107 Cardiovascular-Renal Drugs Antihypertensive Agents BASIC PHARMACOLOGY OF ANTIHYPERTENSIVE HYPERTENSION AGENTS - Systolic blood pressure of 140 or greater or  Drugs that alters sodium & water balance: diastolic blood pressure of 90 or greater. Diuretics Risk Factors  Drugs that alter Sympathetic Nervous System  Smoking function: Sympathoplegic Agents  Metabolic syndrome  Direct Vasodilators: Agents that block  Manifestations of end-organ damage at the time of production or action of angiotensin diagnosis DIURETICS  Family history  Lowers BP by depleting the body of sodium Table 11-1. Classification of hypertension on the basis stores and reducing blood volume or other of blood pressure. mechanisms Systolic/Diastolic Pressure Category  Increase urine excretion 5 mEq/L  Rheumatic heart disease o Hypocalcemia- < 4.5 mEq/L  Ischemic heart disease o Hypomagnesia- < 2.5 mEq/L  Hypoxia  Electrocardiography  Acidosis & alkalosis o Electrical activity occurring during  Electrolyte abnormalities depolarization- repolarization, can be  Excessive catecholamine exposure transmitted through electrodes  Autonomic influence attached to the body & transformed by  Drug toxicity an electrocardiograph (EKG/ECG)  Overstretching of cardiac fiber machine into a series of waveforms.  P wave TREATMENT o reflects atrial depolarization  PR interval FOUR CLASSES OF ANT IARRHYT HMIC o Represents the spread of the impulse AGENT S from the atria through the Purkinje fibers.  QRS complex CLASS 1 o Reflects ventricular depolarization  Action is sodium channel blockade. (Phase 0). Subclasses of this action reflects on the action  ST segment potential duration (APD) & the kinetics of the o Represents phase 2 of the action sodium channel blockade. potential, the absolute refractory  IA period. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 3  MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Pharmacology II o Action prolongs the APD and  It has a direct depressant effects on SA & AV dissociate from the channel with nodes. intermediate kinetics.  Cardiotoxic  IB o Includes excessive potential o Action shorten the and in some prolongation, QT interval prolongation tissues of the heart & dissociate from & induction of torsades de pointes the channel with rapid kinetics. arrhythmia & syncope. Lupus  IC erythematosus- like syndrome o Action have minimal effects on the consisting of arthralgia & arthritis APD & dissociate from the channel  NAPA with slow kinetics.  USES: o Atrial & ventricular arrhythmias. 2nd CLASS 2 and 3rd drug of choice in sustained ventricular arrhythmias associated  Sympatholytic action. Reduces beta with acute MI. adrenergic activity in the heart. IA- QUINIDINE CLASS 3  Similar to procainamide but more toxic.  Action manifests as prolongation of the APD.  Cinchonism; torsades de pointes Most drugs with this action block the rapid  Rarely used for arrhythmias component of the delayed rectifier potassium  Malaria current.  Effects includes: GI effects, H/A, dizziness, tinnitus CLASS 4 IA- DISOPYRAMIDE  Action is blockade of the cardiac calcium channel. This action slows conduction in  Similar to Procainamide regions where the action potential upstroke is  With antimuscarinic effect but may precipitate calcium dependent. heart failure. CLASS 1 IB- LIDOCAINE  Drugs with local anesthetic action block  Sodium channel blockade sodium channels & reduce sodium current.  Low incidence of toxicity  High degree of effectiveness in arrhythmias associated with MI. PHARMACOKINETICS:  Agent of choice for the termination of  Well absorbed orally; IV; IM ventricular tachycardia & prevention of  Hepatic metabolism ventricular fibrillation after cardioversion.  Half-life: 3 to 4 hours IB- MEXILET INE  The oldest group & still widely used  Active congener of lidocaine, with similar antiarrhythmic agents. action.  Used for ventricular arrhythmias & effective in IA- PROCAINAMIDE relieving chronic pain due to diabetic neuropathy & nerve injury.  Slows conduction velocity & pacemaker rate.  Prolongs action potential duration & dissociate IC- FLECAINIDE from sodium current channel with intermediate kinetics.  Sodium channel blockade JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 4  MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Pharmacology II  A potent blocker of sodium & potassium SOT ALOL channels with slow blocking kinetics.  Used for patients with supraventricular  Well absorbed orally, not metabolized in the arrhythmias, with no antimuscarinic effects. liver & not bound to plasma proteins.  Oral use  Used for the treatment of life-threatening  Half-life: 20 hours ventricular arrhythmias & maintenance of sinus rhythm in patient with atrial fibrillation. IC- PROPAFENONE DRONEDARONE  Orally active but with weak blocking activity. Used for supraventricular arrhythmias.  Common A/E: metallic taste & constipation DOFET ILIDE  Half-life: 5 to 7 hours  Dose: 450- 900 mg/day in 3 divided doses  Prolongs action potential, effected by a dose- dependent blockade of the rapid component of IC- MORICIZINE the delayed rectifier potassium current & the blockade of rectifier potassium current CLASS 2 increases in hypokalemia.  Used in maintenance or restoration of sinus BET A ADRENOCEPT OR BLOCKING AGENT rhythm in atrial fibrillation. PROPRANOLOL IBUT ILIDE  Direct membrane effects & prolongation of  Potassium channel blocker, intravenously action potential duration. used for conversion in atrial flutter & fibrillation  Slows SA node automatically & AV nodal of recent onset. conduction velocity CLASS 4 ESMOLOL VERAPAMIL  Short acting  Administered through IV only  Calcium channel blocker  Used for intraoperative & other acute  Slows SA node automaticity & AV nodal arrhythmia conduction velocity, decreases cardiac contractility & reduces blood pressure. CLASS 3  Used for patients with supraventricular tachycardias hypertension & angina. AMIODARONE DILT IAZEM  Drugs that prolong effective refractory period by prolonging the action potential. OTHER DRUGS  Oral & IV  Used for serious ventricular arrhythmia ADENOSINE  Highly effective for the treatment of SV  A nucleoside that occurs naturally throughout arrhythmias such as atrial fibrillation. the body.  Broad spectrum  Half-life in the blood: < 10 seconds  Amiodarone is a substrate for liver cytochrome  Its mechanism involves activation of an inward CYPCYP3A4 & its levels are increased by rectifier potassium current & inhibition of drugs that inhibit this enzyme, ex. Cimetidine calcium current.  Toxicity: bradycardia, heart block in diseased  Drug of choice for prompt conversion of heart, peripheral vasodilation, pulmonary & paroxysmal supraventricular tachycardia to hepatic toxicity. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 5  MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Pharmacology II sinus rhythm because of its high efficacy & very short duration of action  Less effective in the presence of adenosine receptor blockers such as; theophylline, caffeine. Its effects are potentiated by adenosine uptake inhibitors such as dipyridamole.  Used intravenously  Toxicity flushing, chest tightness, dizziness. MAGNESIUM  Found to have antiarrhythmic effects in patients with normal serum magnesium levels.  Mechanism not known but recognized to influence Na+/K+ -ATPase, sodium channels, certain potassium channels & calcium channels.  Indicated in some patients with torsades de pointes even if serum magnesium is normal. POT ASSIUM  Increases K+ permeability and K+ currents  It slows ectopic pacemakers & slows conduction velocity in heart  Used for patients with digitalis-induced arrhythmias & arrhythmias associated with hypokalemia.  Toxicity includes re-entrant arrhythmias, fibrillation or arrest in overdose. REFERENCES Book: Katzung B.G. et al. Basic and Clinical Pharmacology, 14th edition Notes from the discussion of: Anna Liza D. JAMIAS, RPh. RN. Central Philippine University PowerPoint presentation: College of Pharmacy JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 6  Pharmacology II MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Lecture TOPIC OUTLINE Table 13-1 Therapies used in heart failure. I. Drugs Used in Heart Failure a. Heart Failure Chronic Systolic Heart Acute Heart Failure i. Proteins Failure ii. Pathophysiology of Heart Diuretics Diuretics Failure iii. Primary Signs and Aldosterone receptor Vasodilation Symptoms of All Types of antagonists Heart Failure Angiotensin-converting Beta agonists iv. Primary Factors of Cardiac enzyme inhibitors Performance b. Treatment Angiotensin receptor Bipyridines i. Cardiac Glycosides blockers ii. Bipyridines Beta blockers Natriuretic peptide iii. Beta-Adrenoceptor Agonists Cardiac glycosides Left ventricular assist iv. Investigational Positive device Inotrophic Drugs Vasodilators, neprilysin v. Diuretics inhibitor vi. ACE Inhibitors, ARBs, And Other Related Agents Resynchronization and vii. Vasodilators cardioverter therapy viii. Beta Blockers PROT EINS c. Management of Chronic Heart Failure i. Sodium Removal ACT IN ii. ACE Inhibitors iii. ARBs  An important contributor to the contractile iv. Vasodilators property of muscle and other cells. v. Beta Blockers and Ion  A protein that produces small contractile Channel Blockers filaments within muscle cells. vi. Digitalis d. Management of Acute Heart Failure DRUGS USED IN MYOSIN  A protein that produces thick, contractile filaments within muscle cells. HEART FAILURE  A molecular motor & converts chemical energy released from ATP into mechanical energy, thus generating force and movement. HEART FAILURE When contractility of the heart decrease, lesser  Occurs when cardiac output is inadequate to blood pumped >> affecting blood circulation, provide the oxygen needed by the body. progressing into heart failure.  Common cause: o CAD o HPN  2 Major Types o Systolic Failure o Diastolic Failure JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 1  MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Pharmacology II  Neurohumoral compensation: o Sympathetic nervous system o Renin-angiotensin-aldosterone hormonal response PAT HOPHYSIOLOGY OF HEART FAILURE PRIMARY FACTORS OF C ARDIAC  Coronary artery disease PERFORMANCE  Cardiac output below normal range.  Systolic dysfunction  Preload o With reduced cardiac output &  Afterload significantly reduced ejection function,  Contractility is typical of acute failure, especially  Heart Rate resulting from myocardial infarction.  Diastolic dysfunction TREATMENT o Often occurs as a result of hypertrophy and stiffening of the CARDIAC GLYCOSIDES myocardium. DIGOXIN PRIMARY SIGNS AND SYMPT OMS OF ALL TYPES OF HEART FAILU RE o Digitalis lanata o Other source:  Tachycardia  Oleander  Decreased exercise tolerance  Lily of the Valley  SOB  Milkweed  Cardiomegaly o 65-80% absorption  Peripheral edema o Half-life: 36-40 hours  Pulmonary edema JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 2  MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Pharmacology II ISAT AROXIME  Increases contractility by inhibiting Na+/ K+ - ATPase but in addition, it appears to facilitate sequestration of Ca2+ by the SR LEVOSIMERDAN  A drug that sensitizes the troponin system to calcium, also appears to inhibit phosphodiesterase and to cause some o All therapeutically useful cardiac vasodilation in addition to its inotropic effects. glycosides  Inhibit Na+/K+- ATPase- the OMECAMT IV MECARBIL membrane bound transporter  Parenteral agent that activates cardiac myosin  Its inhibitory action is and prolongs systole without increasing responsible of the therapeutic oxygen consumption of the heart. effect (positive inotrophy) as well as its toxicity. DIURET ICS o Increases cardiac contractility (Positive inotrophy effect) FUROSEMIDE BIPYRIDINES  Drug of choice in heart failure  Reduces salt and water retention, edema, and MILRINONE symptoms  Have no effect on cardiac contractility.  A bipyridine compound that inhibits  It reduces venous pressure and ventricular phosphodiesterase isozyme e (PDE-3). preload.  Oral and parenteral use  Half-life: 3-6 hours  It increases myocardial contractility by SPIRONOLACT ONE & EPL ERENONE increasing inward calcium flux in the heart o The aldosterone antagonist diuretic during the action potential. with additional benefit of decreasing  Inhibition of phosphodiesterase results in an morbidity in patient with severe heart increase in cAMP and the increase in failure who are also receiving ACE contractility and vasodilation. inhibitors. BET A-ADRENOCEPT OR AGONIST S ACE INHIBIT ORS, ARB s, AND OT HER RELAT ED AGENT S DOBUT AMINE  Selective beta 1 agonist- widely used in patient CAPT OPRIL with heart failure.  Reduces peripheral resistance thereby  Parenteral drug which produces an increase in reduces afterload cardiac output together with a decrease in  Also reduces salt, and water retention and in ventricular filling pressure. that way reduces preload.  Also used in acute heart failure and helpful if  Also reduces long-term remodeling of the there is a need to raise blood pressure. heart and vessels, an effect that may be responsible for the observed reduction in INVEST IGAT IONAL POSIT IVE INOT ROPHIC mortality and morbidity. DRUGS JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 3  MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Pharmacology II LOSART AN B I Symptoms ACEI/ARB, B  An angiotensin AT1 receptor which appears to with severe blocker, exercise diuretic have similar beneficial effects. C II/III Symptoms Add with aldosterone ALISKIREN marked antagonist, (class II) or digoxin; CRT,  A renin inhibitor approved for HPN, was found mild (class ARNI, to have no definitive benefit in clinical trials for III) exercise hydralazine/ heart failure. nitrate4 D IV Severe Transplant, VASODILAT ORS symptoms LVAD at rest  Effective for the treatment of heart failure because they provide a reduction in preload or MANAGEMENT OF CHRONIC HEART reduction in afterload or both. FAILURE  Treatment of patients at high risk (stages A NESIRIT IDE and B) should be focused on control of  A synthetic form of the endogenous peptide hypertension, arrhythmias, hyperlipidemia and brain natriuretic peptide (BNP) diabetes.  Approved for use in acute cardiac failure.  A recombinant product with increase cGMP in SODIUM REMOVAL smooth muscle cells and reduces venous and arteriolar tone in experimental preparations.  Dietary salt restriction  Short half-life: 18 minutes.  Diuretics o Thiazide diuretics BET A BLOCKERS o Loop diuretics o Spironolactone o Eplerenone BISOPROLOL, CARVEDIL OL, MET OPROLOL, NEBIVOLOL ACE INHIBIT ORS  Most patients with chronic heart failure  Drug of choice in patients with left ventricular responds to these drugs. dysfunction without edema.  They precipitate acute decompensation of  First-line therapy for chronic heart failure cardiac function.  By reducing preload and afterload in  Mechanisms includes attenuation of the asymptomatic patients, ACE inhibitors adverse effects of high concentrations of (enalapril) slow the progress of ventricular catecholamines (including apoptosis), up- dilation and thus slow the downward spiral of regulation of beta receptors, decreased heart the heart failure rate, and reduced remodeling through inhibition of the mitogenic activity of ARBs catecholamines.  Are used to patients who cannot tolerate ACE Table 13-3 Classification and treatment of inhibitors. chronic heart failure. VASODILAT ORS ACC/AH NYHA Descriptio Management A Stage1 Class2 n A Prefailur No Treat obesity, VENODILATORS e symptoms hypertension, but risk diabetes, ISOSORBIDE DINITRATE factors hyperlipidemi present3 a, etc. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 4  MODULE 1: Cardiovascular, Renal and Hematologic Pharmacology Pharmacology II  For patients with high filling pressures with REFERENCES dyspnea, helpful in reducing filling pressure Book: and the symptoms of pulmonary congestion. Katzung B.G. et al. Basic and Clinical Pharmacology, 14th edition Notes from the discussion of: ART ERIOLAR DILATOR Anna Liza D. JAMIAS, RPh. RN. Central Philippine University PowerPoint HYDRALAZINE presentation: College of Pharmacy  Used in patients whom fatigue due to low left ventricular output is the primary symptoms, and helpful in increasing forward cardiac output. BET A BLOCKERS AND IO N CHANNEL BLOCKERS BISOPROLOL, CARVEDILO L, MET OPROLOL, NEBIVOLOL  Therapy using these drugs are based on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart contribute to the downward course of heart failure. DIGIT ALIS  Indicated for patients with heart failure and atrial fibrillation.  Given only when diuretics and ACE inhibitors failed to control the symptoms MANAGEMENT OF ACUTE H EART FAILURE  Occurs frequently in patients chronic failure associated with: o Increased exertion o Increased emotion o Excess salt intake o Nonadherence to therapy or o Increased metabolic demand occasioned by fever, anemia, etc.  Treatment- intravenous treatment of the following: o Diuretics o Dopamine or Dobutamine o Levosimendan o Vasodilators o Conivaptan JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 5  Pharmacology II MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Lecture TOPIC OUTLINE I. Drugs Used in Dyslipidemia a. Hyperlipidemia i. Atherosclerosis b. Pathophysiology of Hyperlipoproteinemia i. Normal Lipoprotein Metabolism c. Synthesis & Catabolism i. Chylomicrons  The major clinical sequelae of ii. VLDL HYPERLIPIDEMIAS are: iii. LDL iv. LP (a) o Acute pancreatitis v. HDL o Atherosclerosis d. Lipoprotein Disorders i. Primary AT HEROSCLEROSIS Hypertriglyceridemias ii. The Primary  Is the leading cause of death for both genders Hypercholesterolemias in the US & other Western countries. e. Dietary Management of  Characterized by yellowish plaques of Hyperlipoproteinemia cholesterol, lipids & cellular debris is the f. Treatment i. Statins walls of large & medium sized arteries, ii. Fibrates resulting in reduced circulation, the major iii. Niacin cause it coronary heart disease such as iv. Bile Acid-Binding Resins angina pectoris or myocardial infarction. v. Inhibitors of Intestinal Steprol Absorption LIPOPROT EINS vi. Inhibition of Microsomal Triglyceride Transfer  That contains apoliprotein (apo) B-100 convey Protein lipids into the artery walls. vii. Antisense Inhibition of apo B-100 Synthesis o Low density lipoprotein (LDL) viii. PCSK9 Inhibition  Major parts of blood DRUGS USED IN cholesterol (harmful to individuals) o Intermediate density lipoprotein (IDL) o Very low density lipoprotein (VLDL) DYSLIPIDEMIA  Secreted by the liver o Lipoprotein (a) –Lp (a) o Remnants of lipoprotein HYPERLIPIDEMIA CELLULAR COMPONENTS IN  Plasma lipids AT HEROSCLEROT IC PLAQUES OR o Are transported in complexes called AT HEROMAS LIPOPROTEINS.  Hyperlipoproteinemias or Hyperlipidemias o Foam cells o Metabolic disorders that involve  These are transformed elevation s in any lipoprotein species. macrophages o It denotes increased levels of o Smooth muscle cells filled with triglycerides. cholesteryl esters.  The atheroma grows with the accumulation of foam cells, collagen, fibrin, and frequently calcium.  HDL JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 1  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II o Exert several anti-atherogenic effects.  The transit the thoracic duct to the blood They participate in retrieval of stream. cholesterol from the artery wall and  Triglycerides are removed from the inhibit the oxidation of atherogenic chylomicrons in extrahepatic tissues through a lipoproteins. pathway shared with VLDL that involves  Low levels of HDL hydrolysis by the lipoproteins lipase (LPL) (Hypoalphalipoproteinnemia) system o Are independent risk factor for atherosclerotic disease. VLDL  Cigarette smoking o A major risk factor for coronary  Secreted by the liver & export triglycerides to disease, it is associated with: peripheral tissues.  Reduced levels of HDL  VLDL triglycerides are hydrolysed by LPL,  Impairment of cholesterol yielding free fatty acid for storage in adipose retrieval tissue & for oxidation in tissues such as  Cytotoxic effect on the cardiac & skeletal muscle. endothelium  Increased oxidation of LDL lipoproteins  Catabolized chiefly by hepatocyte and other  Stimulation of thrombogenesis cells after receptor mediated endocytosis.  Diabetes  Cholesteryl esters from LDL are hydrolysed, yielding free cholesterol for the synthesis of PATHOPHYSIOLOGY OF cell membranes. HYPERLIPOPROTEINEMIA  Cells also obtain cholesterol by synthesis via a pathways involving the formation of mevalonic NORMAL LIPOPROTEIN MET ABOLISM: acid by HMG-CoA reductase. LIPOPROT EINS LP (A)  Have hydrophobic core regions containing  Formed from LDL and the (a) protein, linked cholesteryl esters & triglycerides surrounded by a disulphide bridge. by unsterified cholesterol, phospholipids &  (a) Protein is highly homologous with apoproteins. plasminogen, but is not activated by tissue plasminogen activator. Certain lipoproteins contains very high molecular  Found in atherosclerotic plaques and weight B proteins that exist in 2 forms: contributes to coronary disease by inhibiting thrombolysis.  B-48 o Formed in the intestines, found in HDL chylomicrons & their remnants.  B-100  The apoproteins of HDL are secreted largely o Synthesized in the liver, found in by the liver & intestine VLDL, VLDL remnants, IDL, LDL & Lp  Much of the lipid comes from the surface (a) lipoproteins. monolayers of chylomicrons & VLDL during lipolysis. SYNTHESIS & CAT ABOLISM  HDL also acquires homeostasis of cells. CHYLOMICRONS  Are formed in the intestine & carry triglycerides of dietary origins, unsterified cholesterol & cholesteryl esters. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 2  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II Table 35-1 The primary Hyperlipoproteinemias and  The lipemia is aggravated by estrogens their treatment. because they stimulate VLDL production & pregnancy may cause marked increases in triglycerides despite strict dietary controls.  Management: o Restriction of total dietary fat and abstention from alcohol. o Niacin, fibrate or marine omega-3 fatty acids if VLDL is increased. o Apo C-III antisense is a potential adjunct to therapy. FAMILIAL HYPERT RIGLYCERIDEMIA  Many patients have centripetal obesity with insulin resistance.  Other factors includes: o Alcohol & estrogen, which increase the secretions of VLDL aggravate the lipemia.  Management: LIPOPROTEIN DISORDERS o Dietary with restriction of total fat o Avoidance of alcohol & exogenous PRIMARY HYPERT RIGLYCERIDEMIAS estrogens o Weight reduction  Associated with increased risk of coronary o Exercise disease. o Omega-3 fatty acids supplement  Chylomicrons, VLDL and IDL are found in o Fibrate atherosclerotic plaques. o Niacin, if insulin resistance is not  Patients with triglycerides above 700mg/dL present. should be treated to prevent acute pancreatitis because the LPL clearance mechanism is FAMILIAL COMBINED saturated at about the level. HYPERLIPOPROT EINEMIA (FCH):  Hypertriglyceridemia is an important component of the metabolic syndrome which  A disorder associated with an increased includes insulin resistance, hypertension, and incidence of coronary disease. abdominal obesity.  Increased levels of VLDL, LDL, or both & the  Management: pattern may change with time. o Fibrate + metformin + another  Involves an approximate doubling in VLDL antidiabetic agent secretions & appears to be transmitted as a dominant trait.  Management: PRIMARY CHYLOMICRONEMIA o Reductase inhibitor alone or in  Not present in the serum of normal individuals combination with niacin or fenofibrate. who have fasted for 10 hours. In this combination, pravastatin or  Caused by LPL deficiency or defects, rosuvastatin is recommended because apolipoprotein C II deficiency or the presence neither is metabolized via CYP3A4. of an inhibitor of LPL. o Marine omega-3 fatty acids.  Patients may have eruptive xanthomas, hepatosplenomegaly, hypersplenism, & lipid- FAMILIAL DYSBET ALIPO PROT EINEMIA laden foam cells I bone marrow, liver and spleen. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 3  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II  Characterized by accumulation of remnants of Glycogen storage Corticosteroid excess triglyceride-rich lipoproteins such as disease chylomicrons & VLDL in the plasma Hypopituitarism Androgen overdose  Patients develop tuberous or tuberoeruptive xanthomas or characteristic planar xanthomas Acromegaly of the palmar creases. Immunoglobulin-  Management: lipoprotein complex o Weight loss, decrease fat, cholesterol disorders & alcohol consumption Lipodystrophy o Fibrate or niacin Protease inhibitors, o Reductase inhibitor tacrolimus, sirolimus, other drugs THE PRIMARY HYPERCHO LEST EROLEMIAS LDL RECEPTOR DEFICIENT DIET ARY MAN AGEMENT OF HYPERLIPOPROTEINEMIA FAMILIAL HYPERCHOLESTEROLEMIA (FH)  Management:  An autosomal sominant trait o Drug therapy + Diet  Cholesterol level ranges from 260-500 mg/dL  Total fat, sucrose, fructose increases VLDL.  Triglycerides are usually normal, tendon  Alcohol can cause significant xanthomas are often present. hypertriglyceridemia by increasing hepatic  Management: secretion of VLDL. o Niacin, ezetimibe, reductase inhibitiors  The diet suffices for management can be o Emerging therapies includes made only after weight has stabilized for at Mipomersen, lomitapide, monoclonal least 1 month. antibodies.  Use complex carbohydrates and fiber.  Cis-monounsaturated fats should predominate. FAMILIAL LIGAND-DEFECTIVE  Weight reduction, caloric restriction & APOLIPOPROTEIN B-100 avoidance of alcohol.  Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of TREATMENT LDL leading to hypercholesterolemia of moderate severity. ST AT INS  Tendon xanthomas may occur  HMG-CoA reductase inhibitors  Reductase inhibitor response is variable  It inhibits the enzyme for cholesterol synthesis.  Most potent lipid lowering medications for TABLE 35-2 Secondary causes of monotherapy & considered the first choice in hyperlipoproteinemia. managing high cholesterol. Hypertriglyceridemia Hypercholesterolemia  Example: Diabetes mellitus Hypothyroidism o Lovastatin o Atorvastatin Alcohol Ingestion Early nephrosis o Fluvastatin Severe nephrosis Resolving lipemia o Pravastatin Estrogens Immunoglobulin- o Simvastatin lipoprotein complex o Rosuvastatin disorders o Pitavastatin. Uremia Anorexia nervosa HIV infection Cholestasis Myxedema Hypopituitarism JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 4  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II  Useful alone or with resins, niacin or ezetimibe in reducing levels of LDL. PRECUATIONS OR CONTRAINDICATIONS:  Pregnant women with hyperlipidemia, lactating or likely to become pregnant, children, hepatic or renal disease, existing myalgia or muscle weakness. DOSE  Should be given in the evening, except for atorvastatin, rosuvastatin & Pitavastatin. FIBRAT ES  Ex. Gemfibrozil & Fenofibrate  It decreases levels of VLDL & LDL in some patients. LOVAST AST IN & SIMVAST AT IN GEMFIBROZIL  Are inactive lactone prodrugs  Is absorbed from the intestine that are hydrolysed in the GIT and bound to plasma proteins. to the active beta-hydroxyl  It undergoes enterohepatic derivatives. circulation & readily passes the placenta. PRAVAST AT IN FENOFIBRAT E  Has an open, active lactone ring.  Is an isopropyl ester that is hydrolysed completely in the intestine. AT ORVAST AT IN, FLUVAST AT IN &  Fibrates function primarily as ROSUVAST AT IN ligands for the nuclear  Are fluorine-containing transcription receptor PPAR-a. congeners that are active as They transcriptionally given. upregulate LPL, apo A-II, and they downregulate apo-C-III, HMG-COA REDUCT ASE an inhibitor of lipolysis.  The fibrate of choice for use in  Mediates the first committed combination with statin. step in sterol biosynthesis  Fibrates are useful in the hypertriglyceridemias in which VLDL HMG-COA REDUCT ASE INHIBITORS predominate & dysbetalipoproteinemia.  Block the enzyme HMG-CoA  Dose: reductase that is responsible o Gemfibrozil= 600mg once or BID for the synthesis of cholesterol orally; fenofibrate= 1 to 3, 48mg tab in the liver. It binds to the daily active site of the enzyme and  Absorption of gemfibrozil is improved with change its structure. food.  Toxicity: USES JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 5  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II o Rashes, GI symptoms, myopathy, o Should be given 1 hour before or at arrhythmias, hypokalemia, & high least 2 hours after resin, to ensure blood levels of aminotransferases or adequate absorption. alkaline phosphatase.  Toxicity: o Constipation, bloating, heartburn, NIACIN diarrhea, steatorrhea, increased formation of gallstones.  Decreases triglycerides and LDL levels and Lp (a) in most patients and raises HDL cholesterol INHIBITORS OF INT EST INAL ST EPROL levels. ABSORPT ION  Niacin is converted in the body to the amide which is incorporated into niacinamide adenine dinucleotide (NAD). EZET IMIBE  Niacin inhibits VLDL secretion, in turn  Selectively inhibits intestinal absorption of decreasing production of LDL. It also inhibits phytosterol and cholesterol. A transport the intracellular lipase of adipose tissue via protein, NPC1L1, is the target of the drug. receptor-mediated signaling.  Readily absorbed & conjugated in the intestine  Uses: to an active glucuronide, reaching peak blood o In combination with a resin or levels in 12-14 hours. reductase inhibitor, it normalizes LDL  Dose in most patients with heterozygous o 5-20mg/d familial hypercholesterolemia.  Use: o The most effective agent for o For hypercholesterolemia; increasing HDL and reductases Lp (a) phytosterolemia  Toxicity:  Toxicity: o Pruritus, rashes, dry skin or mucous o Myositis membranes, acanthosis nigricans, tachyphylaxis. INHIBIT ION OF MICROSOMAL TRIGLYCERIDE TRANSFER PROT EIN BILE ACID-BINDING RESINS  It plays an essential role in the addition of  Ex. Colestipol, cholestyramine, and triglycerides to nascent VLDL in liver, and to Colesevelam chylomicrons in the intestine.  Useful only for isolated increases in LDL, and  LOMITAPIDE in patients who also have hypertriglyceridemia. o An MTO inhibitor  These agents are large polymeric cationic exchange resins that are insoluble in water. ANT ISENSE INHIBIT ION OF APO B-100 They bind bile acids in the intestinal lumen and SYNT HESIS prevent their reabsorption, but the resin itself is not absorb.  Mipomersen  Bile acids, metabolites of cholesterol, are o An antisense oligonucleotide that normally efficiently reabsorbed in the jejunum targets apo B-100 mainly in the liver and ileum. Apo B-100 is also transcribed in the  Excretion is increased up to tenfold when retina and in the cardiomyocytes. resins are given, resulting in enhanced conversion of cholesterol to bile acids in liver PCSK9 INHIBIT ION via 7 a-hydroxylation, which is normally  Evolocumab, alirocumab controlled by negative feedback by bile acids. o Inhibits catabolism of LDL receptor.  Uses: Use of these agents is restricted to o For the treatment of patients with patients who have familial primary hypercholesterolemia; for the hypercholesterolemia or clinical treatment of LDL. atherosclerosis cardiovascular disease JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 6  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II who require additional reduction of LDL. REFERENCES Book: Katzung B.G. et al. Basic and Clinical Pharmacology, 14th edition Notes from the discussion of: Anna Liza D. JAMIAS, RPh. RN. Central Philippine University PowerPoint presentation: College of Pharmacy JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 7  Pharmacology II MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Lecture TOPIC OUTLINE  Anemia I. Agents Used In Cytopenias; o A deficiency in oxygen-carrying Hematopoietic Growth Factors erythrocytes, is the most common a. Hematopoiesis deficiency and several forms are i. Bone Marrow easily treated. b. Agents Used In Anemias i. Iron o Sickle cell anemia -a condition ii. Vitamin B12 resulting from a genetic alteration in iii. Folic Acid the hemoglobin molecule, is common iv. Hematopoietic Growth but is not easily treated. Factors  Thrombocytopenia CHAPTER 33: o Occurs when your blood platelet count is low. o Platelets AGENTS USED IN  Also called thrombocytes.  This type of blood cell clumps together to form blood clots to CYTOPENIAS; help stop bleeding at the site of a cut or wound. HEMATOPOIETIC Thrombocytopenia and neutropenia are not rare, and some forms are amenable to drug therapy. GROWTH FACTORS AGENTS USED IN ANEMIAS IRON HEMATOPOIESIS  The production from undifferentiated stem BASIC PHARMACOLOGY cells and circulating erythrocytes, platelets and leukocytes, is a remarkable process that produces more than 200 billion new blood cells per day in normal person and even greater number of cells in persons with conditions that causes loss or destruction of blood cells. BONE MARROW  hematopoietic machinery -resides primarily in the bone marrow in adults and requires a constant supply of three essential nutrients—  Essential nutrients:  Iron forms the nucleus of the iron-porphyrin o Iron heme ring which together with globin chains o vitamin B12, and forms haemoglobin. o folic acid—as well as the presence of  Hemoglobin o Hematopoietic growth factors o Reversibly binds oxygen and provides (proteins that regulate the proliferation the critical mechanism for oxygen and differentiation of hematopoietic delivery from the lungs to other cells.) tissues. Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 1  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II  Iron in other foods especially vegetables and grains, is tightly bound to organic compounds and are less absorbed.  Iron crosses the luminal membrane of the intestinal mucosal cell by 2 mechanisms: o active transport of ferrous iron (Fe2+) by the divalent metal transporter DMT1, o absorption of iron complexed with heme  The newly absorbed iron can be actively transported into the blood across the  Iron deficiency: basolateral membrane by a transporter known o The most common cause of chronic as ferroportin and oxidized to ferric iron (Fe3+) anemia. by the ferroxidase hephaestin.  Like other forms of chronic anemia, iron deficiency anemia leads TRANSPORT, STORAGE, & ELIMINATION o Pallor  Intestinal epithelial cells as ferritin, a water o Fatigue soluble complex consisting of a core of ferric o Dizziness hydroxide covered by a shell of a specialized o Exertional dyspnea storage protein called apo-ferritin. o Tissue hypoxia  Iron is transported in the plasma bound to  Daily requirement transferrin (a β-globulin that can bind two o Small amount which can easily fulfilled molecules of ferric iron.) by the iron available in a wide variety  There is no mechanism for excretion of of food. iron. o Small amounts are lost in the feces by PHARMACOKINET ICS exfoliation of intestinal mucosal cells, and trace amounts are excreted in  Free inorganic iron is extremely toxic, but iron bile, urine, and sweat. is required for essential proteins such as hemoglobin; therefore, evolution has provided an elaborate system for regulating iron CLINICAL PHARMACOLOG Y absorption, transport, and storage.  The system for regulating iron uses INDICATION specialized transport, storage,  The use of iron preparations is the treatment ferrireductase, and ferroxidase proteins or prevention of iron deficiency anemia. whose concentrations are controlled by the  This manifests as a hypochromic, microcytic body’s demand for hemoglobin synthesis and anemia in which the erythrocyte mean cell adequate iron stores volume (MCV) and the mean cell hemoglobin  Hepcidin concentration are low. o A peptide, produced primarily by liver  Iron deficiency is commonly seen in cells, serves as a key central regulator populations with increased iron of the system. requirements. o Infants, especially premature infants; ABSORPTION o children during rapid growth  Iron in meat proteins can be absorbed periods; efficiently because heme iron in meat o pregnant and lactating women; hemoglobin and myoglobin can be absorbed o And patients with chronic kidney intact without first having to be dissociated into disease who lose erythrocytes at a elemental iron. relatively high rate during JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 2  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II hemodialysis and also form them at a PARENTERAL THERAPY high rate as a result of treatment with  Patients with documented iron deficiency who the erythrocyte growth factor are unable to tolerate or absorb oral iron erythropoietin.  Patients with extensive chronic anemia who TABLE 33-3 Some commonly used oral iron cannot be maintained with oral iron alone preparations. 3 FORMS OF PARENTERAL IRON Preparation Tablet Elemental Usual o Iron dextran Size Iron per Adult o Sodium ferric gluconate complex Tablet Dosage o lron sucrose for  Iron dextran Treatment o A stable complex of ferric of Iron oxyhydroxide and dextran polymers Deficiency containing 50 mg of elemental iron per (Tablet per Day) milliliter of solution. It can be given by deep intramuscular injection or by Ferrous 325 mg 65 mg 2–4 intravenous infusion, although the sulfate, hydrated intravenous route is used most commonly. Ferrous 200 mg 65 mg 2–4  Sodium ferric gluconate complex & lron sulfate, desiccated sucrose o Alternative parenteral iron Ferrous 325 mg 36 mg 3–4 preparations. gluconate  Ferric carboxymaltose Ferrous 325 mg 106 mg 2–3 o A colloidal iron preparation embedded fumarate within a carbohydrate polymer.  Ferumoxytol TREATMENT o A superparamagnetic iron oxide  Iron deficiency anemia is treated with oral or nanoparticle coated with carbohydrate. parenteral iron preparations.  Oral iron corrects the anemia just as rapidly CLINICAL T OXICIT Y and completely as parenteral iron in most cases if iron absorption from the ACUTE TOXICITY gastrointestinal tract is normal.  Accidental ingestion of children ORAL IRON THERAPY  10 tablets —lethal for young children  A wide variety of oral iron preparations is  Children who are poisoned with oral iron experience available. Because ferrous iron is most o necrotizing gastroenteritis with efficiently absorbed, ferrous salts should be vomiting, used. Ferrous sulfate, ferrous gluconate, and o abdominal pain ferrous fumarate are all effective and o bloody diarrhea inexpensive and are recommended for the o shock treatment of most patients. o lethargy COMMON ADVERSE EFFECTS o Dyspnea.  Management:  Nausea o Whole bowel irrigation -flush out  Epigastric discomfort unabsorbed pills.  Abdominal cramps o Deferoxamine -potent iron-chelating  Constipation compound, can be given intravenously  Diarrhea to bind iron that has already been JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 3  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II absorbed and to promote its excretion in urine and feces. o Activated charcoal –ineffective (does not bind iron) DON’T GIVE! o supportive therapy –for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided CHRONIC IRON TOXICITY  Chronic iron toxicity (iron overload), also known as hemochromatosis, results when  Active forms in humans excess iron is deposited in the heart, liver, o Deoxyadenosylcobalamin pancreas, and other organs. It can lead to o Methylcobalamin organ failure and death.  Vitamin B12 in foods  Treatment o Cyanocobalamin o Intermittent phlebotomy –most o Hydroxocobalamin efficiently treatment  Both are available vitamin B12 o Deferoxamine –(parenteral) Iron parenteral injection chelation therapy  The ultimate source of vitamin B12 is from o Deferasirox & Deferiprone -the oral microbial synthesis; the vitamin is not iron chelators synthesized by animals or plants.  The chief dietary source of vitamin B12: Note: Deferoxamine; Deferasirox; and Deferiprone o meat (especially liver) –less efficient as well as more complicated, o eggs expensive, and hazardous, but it may be the only o dairy products option for iron overload that cannot be managed  intrinsic factor by phlebotomy, as is the case for many individuals o A protein secreted by the stomach that with inherited and acquired causes of refractory is required for gastrointestinal uptake anemia such as thalassemia major, sickle cell of dietary vitamin B12. anemia, aplastic anemia, etc. PHARMACOKINET ICS VIT AMIN B12  Two essential enzymatic reactions in humans  Cobalamin require vitamin B12  Serves as a cofactor for several essential o methylcobalamin serves as an biochemical reactions in humans. intermediate in the transfer of a methyl  Sometimes called extrinsic factor group from N5-methyltetrahydrofolate  Deficiency will lead to: to homocysteine, forming methionine o Megaloblastic anemia o isomerization of methylmalonyl-CoA to o Gl symptoms succinyl-CoA by the enzyme o Neurologic abnormalities methylmalonyl-CoA mutase CHEMIST RY ABSORPTION  Vitamin B12 consists of a porphyrin-like ring  Vitamin B12 is absorbed after it complexes with a central cobalt atom attached to a with intrinsic factor, a glycoprotein secreted by nucleotide. the parietal cells of the gastric mucosa.  Once absorbed, it is transported to the various cells of the body bound to a family of specialized glycoprotein, transcobalamin I, II, & Ill. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 4  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II  Excess vitamin B12 is stored in the liver.  Folic acid (pteroylglutamic acid) is composed of a heterocycle (pteridine), p-aminobenzoic CLINICAL PHARMACOLOG Y acid, and glutamic acid  Uses FIGURE 33–4 The structure of folic acid. o To treat or prevent deficiency  Megaloblastic anemia  Macrocytic anemia  Leukopenia  Thrombocytopenia  Characteristic hypercellular bone marrow with an accumulation of megaloblastic erythroid and other precursor cells.  Schilling test PHARMACOKINET ICS o Which measures absorption and urinary excretion of radioactively  Sources labeled vitamin B12, can be used to o Yeast further define the mechanism of o Liver vitamin B12 malabsorption when this o Kidney is found to be the cause of the o Green vegetable megaloblastic anemia.  5-20mg of folates is stored in the liver and  The most common causes of vitamin B12 other tissues. deficiency  Folic acid is destroyed by catabolism so serum o pernicious anemia level falls within a few days when intake is o partial or total gastrectomy diminished. o and conditions that affect the distal  Deficiency ileum o Can develop within 1 to 6 months after  malabsorption syndromes the intake of folic acid stops,  inflammatory bowel disease depending on the patient’s nutritional  Small bowel resection. status and the rate of folate utilization. FOLIC ACID PHARMACODYNAMICS  Vitamin B9  Important reactions  Reduced form of folic acid are required for o Produces dTMP needed for DNA essential biochemical reactions that provides synthesis precursors for the synthesis of the ff: o N5-methylenetetrahydrofolate is o Amino acids required for the B12 dependent o Purines reaction that generate methionine from o DNA homocysteine.  Folate deficiency is implicated as a cause of o Tetrahydrofolate cofactors donate one congenital malformations in newborns and carbon unit during the de novo may play in vascular disease. synthesis of essential purines.  Folic acid —is pteroylglutamic acid, composed  Greater folate requirements of heterocycle (pteridine), p-aminobenzoic acid o Patients with haemolytic anemia & glutamic acid.  Maternal folic acid deficiency o Fetal neural tube defects CHEMIST RY JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 5  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II CLINICAL PHARMACOLOG Y o An isoform of erythropoietin covalently attached to a long polyethylene glycol  Folic acid deficiency is often caused by polymer. inadequate dietary intake of folates. o Administered as a single dose IV or  Patients with alcohol dependence and patients SQ dose at 2 weeks or monthly with liver disease can develop folic acid interval. deficiency because of poor diet and diminished  Erythropoietin induces release of reticulocytes hepatic storage of folates. from the bone marrow.  Pregnant women and patients with hemolytic  Endogenous erythropoietin is produced in the anemia have increased folate requirements kidney. and may become folic acid-deficient,  Patient with renal disease, erythropoietin is especially if their diets are marginal. usually low because kidneys cannot produce  Folic acid deficiency can be caused by drugs. growth factors. o Methotrexate o Trimethoprim ERYTHROPOIESIS-STIMULATING AGENTS o Pyrimethamine (ESAs) o Phenytoin  1 mg of folic ac id orally is sufficient to reverse o Consistently improve the hematocrit megaloblastic anemia, restore normal serum and hemoglobin level, often eliminate folate levels and replenish body stores of the need for transfusions, and reliably folates in all patients. improve quality of life indices.  Used in anemia secondary to HEMAT OPOIET IC GROWTH FACT ORS chronic kidney disease  Used illegally by endurance  These are glycoprotein hormones that regulate athletes to enhance the proliferation and differentiation of performance. hematopoietic progenitor cells in the bone  “Blood doping” marrow.  Common adverse effects o Erythropoietin  HPN o Myeloid growth factors  Thrombotic o Megakaryocyte growth factors complications  Colony-stimulating factors  Allergic reactions o The first growth factors identified o They stimulate the growth of colonies MYELOID GROWTH FACTORS of various bone marrow progenitor cells in vitro.  Stimulate proliferation and differentiation by  Known hematopoietic growth factors interacting with specific receptor found on o Erythropoietin myeloid progenitor cells.  Epoetin alfa  G-CSF & GM-CSF  Epoetin beta o two myeloid growth factors currently o Granulocyte colony — stimulating available for clinical use, were factor (G-CSF) originally purified from cultured human o Granulocyte — macrophage colony — cell lines stimulating factor (GM-CSF) o GM-CSF o Interleukin 11 (IL-1)  has broader biologic actions o Thrombopoietin receptor agonists than G-CSF  Romiplostin  It is a multipotential  Eltrombopag hematopoietic growth factor that stimulates proliferation and differentiation of early and ERYT HROPOIET IN late granulocytic progenitor  Methoxy polyethylene glycol — epoetin beta cells as well as erythroid and megakaryocyte progenitors. JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 6  MODULE 2: DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT Pharmacology II  rHuG-CF (Filgrastim) o A thrombopoietin agonist peptide  Produced in a covalently linked to antibody bacterial expression fragments that serve to extend the system. peptide’s half-life.  It is a nonglycosylated  Eltrombopag peptide of 175 amino o An orally active small nonpeptide acids with a molecular thrombopoietin agonist molecule weight of 18 Kda approved for therapy of patients with  Tbo-filgrastim chronic immune thrombocytopenia  Sargramostim who have had an inadequate  Produced in yeast response to other therapies, and for expression system treatment of thrombocytopenia in  Pegfilgrastim (a covalent patients with hepatitis C to allow conjugation product of initiation of interferon therapy. filgrastim and a form of polyethylene glycol, has a REFERENCES Book: much longer serum half-life Katzung B.G. et al. Basic and Clinical than recombinant G-CSF, and Pharmacology, 14th edition it can be injected once per Notes from the discussion of: myelosuppressive Anna Liza D. JAMIAS, RPh. RN. chemotherapy cycle instead of Central Philippine University PowerPoint daily for several days) presentation: College of Pharmacy  Linograstim (used widely in Europe, is a glycosylated form of recombinant G-CSF) o G-CSF  Stimulates proliferation and differentiation of progenitors already committed to the neutrophils lineage  Toxicity o Bone pain o Splenic rupture MEGAKARYOCYT E GROWT H FACT ORS  Patients with thrombocytopenia — high risk of haemorrhage.  Thrombopoietin (TPO)  IL-11 o Recombinant form of IL-11 was the first FDA approved for treatment of thrombocytopenia. o A 65 to 85 kDA protein produced by fibroblasts and stomal cells in the bone marrow. o Toxicity: fatigue, H/A, dizziness, cardiovascular effects  Oprelvekin o Recombinant form of IL-11 approved for clinical use.  Romiplostin JACOMILLE, J.R.L.│BS IN PHARMACY 3– CPU│1ST SEM Page 7