Serotonin Antagonists and Antifibrinolytic Agents PDF

Serotonin Antagonists and Antifibrinolytic Agents Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 1 Objectives Briefly review serotonin receptors Discuss the pharmacology of serotonin antagonists and inhibitors of fibrinolysis 2 Serotonin (5-Hydroxytryptamin...

Serotonin Antagonists and Antifibrinolytic Agents Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 1 Objectives Briefly review serotonin receptors Discuss the pharmacology of serotonin antagonists and inhibitors of fibrinolysis 2 Serotonin (5-Hydroxytryptamine; 5-HT) Receptors 3 Serotonin (5-Hydroxytryptamine; 5HT): Receptors There are currently a total of 14 serotonin receptor subtypes that have been identified 5-HT receptors can be either stimulatory/excitatory (5-HT3 and 5-HT4) or inhibitory ALL 5-HT receptors, EXCEPT 5-HT3 receptors, are G proteincoupled receptors The G protein-coupled 5-HT receptors are coupled to different transmembrane-signaling mechanisms See physiology notes to determine which receptors are linked to which G-protein, effector and second messenger 5-HT3 receptor subtype is a ligand-gated ion channel that gates Na+ and K+ currents 4 Serotonin (5-Hydroxytryptamine; 5HT): 5-HT3 Receptor Subtype 5-HT3 receptor subtype is located in both the central and peripheral nervous systems In the central nervous system: Highest concentration found in the solitary tract nucleus (STN) and area postrema (Chemoreceptor Trigger Zone) In the peripheral nervous system: Extensively distributed on enteric neurons in the GI tract including vagal and splanchnic afferent nerves, as well as other peripheral locations 5-HT3 receptors in BOTH the central and peripheral nervous systems participate in the emetic response and this provides the basis for the anti-emetic property of 5-HT3 receptor antagonists Chemoreceptor trigger zone is very sensitive to drug-induced emesis 5 Pathophysiology of PONV 6 Selective 5-HT3 Receptor Antagonists 7 Selective 5-HT3 Receptor Antagonists Are a group of agents that selectively antagonize the 5-HT3 receptor subtype Main differences are based on their chemical structure, 5-HT3 receptor affinity, and pharmacokinetic profiles Dolasetron, granisetron, ondansetron are considered equally efficacious at equivalent doses for the prevention of nausea/vomiting, the exception being palonosetron There is evidence that palonosetron may be superior to other 5HT3 receptor antagonists in the management of acute/delayed emesis 8 Selective 5-HT3 Receptor Antagonists: Current Available Agents Current available agents 1. 2. 3. 4. 5. Ondansetron (Zofran®) Granisetron (Kytril®) Dolasetron (Anzemet®) Palonosetron (Aloxi®) – is not discussed in Stoelting Alosetron (Lotronex®) – is not discussed in Stoelting Dosage forms Dolasetron, granisetron, and ondansetron are all available in both oral and intravenous dosage forms Palonosetron is only available in an intravenous dosage form Alosetron is an oral only agent that is indicated only for women with severe diarrhea-predominant irritable bowel syndrome. It is NEVER used for prevention/treatment of nausea/vomiting 9 Selective 5-HT3 Receptor Antagonists Mechanism of Action Selectively bind to and inhibit 5-HT3 receptors thereby blocking the binding of serotonin at this receptor subtype and the subsequent nausea/vomiting. Antagonism occurs both peripherally on vagal nerve terminals in the GI tract and centrally in the chemoreceptor trigger zone (area postrema) These agents have little to no affinity for other receptors The anti-emetic effects of these agents persist long after they disappear from the circulation, suggesting their continuing interaction at the receptor level Agents are not effective in the treatment of motion-induced nausea & vomiting and treatment of postoperative nausea & vomiting from vestibular stimulation 10 Selective 5-HT3 Receptor Antagonists: Pharmacokinetics Oral products are readily absorbed & cross the BBB The following are the 5-HT3 antagonists serum t1/2: Dolasetron (Anzemet®): Active metabolite (Hydrodolasetron): Granisetron (Kytril®): Ondansetron (Zofran®): Palonosetron (Aloxi®): < 10min 7.3 hours 9-11 hours 4 hours 40 hours Metabolism All agents are metabolized by different liver CYP 450 enzyme systems to inactive metabolites, with the exception of dolasetron These agents are moderately protein bound Elimination: Hepatic & Renal 11 Selective 5-HT3 Receptor Antagonists Adverse effects Most common: Headache (#1), constipation or diarrhea, drowsiness May also increase liver function tests Can cause dose-dependent QT prolongation Avoid use in patients with congenital long QT syndrome ECG monitoring is recommended in patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation, administer cautiously in patients who have or may develop prolongation of cardiac conduction intervals, particularly the QTc interval Not as big of a concern as with droperidol 12 Selective 5-HT3 Receptor Antagonists Adverse effects (cont.) NEW Warning – the development of serotonin syndrome has been reported with 5-HT3 antagonists. Most reports have been associated with concomitant use of serotonergic agents or with overdose. Some of the reported cases were FATAL 13 Ondansetron (Zofran®) The prototypical selective 5-HT3 receptor antagonist Clinical uses Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy Prevention of postoperative nausea and/or vomiting Not as effective once PONV occurs (treatment) Decreases PONV by ~26% PONV = Post-operative nausea and vomiting 14 Ondansetron (Zofran®) Always READ the labels Dose (PONV prevention) Adult 4 – 8 mg IVP over 2-5 minutes for prophylaxis Pediatric (1 month – 12 years) < 40 kg: 0.1 mg/kg IVP over 2-5 minutes for prophylaxis > 40 kg: 4 mg IVP over 2-5 minutes for prophylaxis In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded Many providers give immediately before induction or 15-30 minutes prior to the end of surgery Think about duration of action and length of surgery when deciding when to administer 15 Ondansetron (Zofran®) Pharmacokinetics Metabolism Extensively metabolized via CYP 450 (several CYP 450 enzyme systems are involved) Main route of elimination is via the liver Excretion only ~5% excreted in the kidney (not dependent upon renal elimination) 16 Ondansetron (Zofran®) Drug-Drug interactions Apomorphine: profound hypotension and loss of consciousness can occur and for this reason ondansetron is contraindicated with concomitant use Adverse effect Most common: Headache (#1), diarrhea, drowsiness/sedation 17 Dolasetron (Anzemet®) Indications The prevention and treatment of postoperative nausea and/or vomiting in adults and children 2 years and older Used in prevention and treatment of chemotherapy-induced nausea and vomiting 18 Dolasetron (Anzemet®) Metabolism After dolasetron is administered, it is rapidly and completely metabolized (t1/2 < 10 min) by plasma carbonyl reductase enzyme to an active metabolite, hydrodolasetron, which is an even more potent selective 5-HT3 receptor antagonist than dolasetron. The primary anti-emetic effects is from hydrodolasetron. Hydrodolasetron is then metabolized by CYP 450 liver enzymes Hydrodolasetron t1/2 = 7.3 hours 19 Dolasetron (Anzemet®) Adult dose PONV prophylaxis: 100 mg PO 2 hrs before surgery, 12.5 mg IV 15 min before surgery or 15 min before the cessation of anesthesia PONV treatment: 12.5 mg IV as soon as nausea or vomiting presents Pediatric age 2-16 y/o dose IV: 0.35 mg/kg IV, with a maximum dose of 12.5 mg, given as a single dose approximately 15 minutes before the cessation of anesthesia (prophylaxis) OR as soon as nausea or vomiting presents (treatment) The IV product can be used for oral administration but the recommended dose is slightly different than below Oral: 1.8 mg/kg up to a maximum 100-mg dose given within 2 hours before surgery 20 Dolasetron (Anzemet®) Use with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly the QTc intervals These include patients with hypokalemia and hypomagnesemia, patients taking diuretics, antiarrhythmics or other drugs known to prolong the QT interval, and patients with congenital QT syndrome Dolasetron prolongs the QT interval in a dose-dependent fashion Adverse effects Headache (#1), dizziness, drowsiness 21 Palonosetron (Aloxi®) A selective 5-HT3 antagonist agent that has the highest affinity for 5-HT3 receptors and longest t1/2 of all the selective 5HT3 antagonists Indication Prevention of acute and delayed CINV Prevention of PONV for up to 24 hours following surgery Not to be used for the treatment of PONV CINV = Chemotherapy induced nausea and vomiting PONV = Post-operative nausea and vomiting 22 Palonosetron (Aloxi®) Dose Post-operative nausea and vomiting 0.075 mg IVP over 10 sec immediately before the induction of anesthesia 23 Palonosetron (Aloxi®) Pharmacokinetics Metabolism: Liver via multiple CYP 450 enzymes t1/2 = 40 hours Excretion: Kidney Adverse effects QT prolongation, bradycardia, headache, constipation 24 INHIBITORS OF FIBRINOLYSIS 25 Antifibrinolytic Agents: Aprotinin (Trasylol®) In November 2007, Bayer suspended the marketing of this drug until final results of the BART study became available. The BART study showed an increase in the risk of death with aprotinin compared with aminocaproic acid and tranexamic acid, consistent with findings from other recent studies Because aprotinin has been shown to decrease the need for red blood cell transfusions in patients undergoing coronary artery bypass surgery, future supplies of aprotinin will continue to be available through the company as an investigational drug under a special treatment protocol 26 Antifibrinolytic Agents: Aprotinin (Trasylol®) A naturally occurring polypeptide that inhibits several serine protease enzymes and is obtained from bovine lung tissue Mechanism of action Aprotinin is a nonspecific agent that acts by forming reversible stoichiometric enzyme inhibitor-complexes and inhibits human trypsin, plasmin, plasma and tissue kallikrein, elastase, urokinase, & thrombin Through its inhibition of multiple mediators, aprotinin inhibits fibrinolysis, inhibits inflammatory mediators & inflammatory responses and reduces thrombin generation. Aprotinin also preserves platelet function 27 Antifibrinolytic Agents: Aprotinin (Trasylol®) The inhibition effects on the various serine protease enzymes by aprotinin are concentration-dependent Inhibits plasmin at low concentrations (antifibrinolytic effects) Inhibits kallikrein at high concentrations (inhibits systemic inflammatory response & antifibrinolytic effects) The effects of aprotinin use in CPB involve a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding Used for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CABG in the course of CABG surgery who are at an increased risk for blood loss and blood transfusion 28 Antifibrinolytic Agents: Aprotinin (Trasylol®) Adverse effects Anaphylactic and anaphylactoid reactions Because aprotinin is derived from bovine origin, the possibility of a hypersensitivity reaction exists Mild skin rashes, urticaria, fatal anaphylactic shock with circulatory failure A test dose of 1 mL (1.4 mg or 10,000 kallikrein inhibitor units) should always be administered at least 10 minutes before the loading dose Atrial fibrillation Fever Renal dysfunction 29 Antifibrinolytic Agents: Lysine Analogs These agents are synthetic derivatives of the amino acid lysine (lysine analogs) that act as potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis These agents are used for the treatment of hyperfibrinolysis, used to decrease postoperative bleeding and reduce the need for transfusions from CABG, orthopedic procedures, liver transplant, tooth extractions in hemophiliacs, and other surgical procedures where fibrinolysis is a mechanism of bleeding 30 Antifibrinolytic Agents: Lysine Analogs (cont.) Current FDA Lysine Analog Products Epsilon Aminocaproic Acid (Amicar®) Tranexamic Acid (Cyklokapron®, Lysteda®) 31 Aminocaproic Acid (Amicar®) Is a synthetic derivative of the amino acid lysine (a lysine analog) that acts as an inhibitor of fibrinolysis Mechanism of action Is a competitive inhibitor of lysine binding sites on plasminogen and prevents the conversion of plasminogen into plasmin. At higher doses, acts as a noncompetitive inhibitor of plasmin directly, blocking the interaction of plasmin with fibrin This results in the inhibition of fibrin degradation which allows for the formation of a more stable clot and decreased risk of recurrent bleeding 32 Aminocaproic Acid (Amicar®) Is available as IV or Oral product Pharmacokinetics Rapidly absorbed almost entirely when given orally Distribution Distributes throughout extravascular and intravascular compartments of the body, penetrating human red blood cells as well as other tissue cells Metabolism: minimal t1/2 = 2 hours Excretion Renal excretion is the primary route of elimination Is rapidly excreted in the urine and thus must be given IV at short intervals to maintain a therapeutic level Use with caution in renal failure patients due to accumulation 33 Aminocaproic Acid (Amicar®) Warnings/Precautions Do not administer without a definite diagnosis of laboratory findings indicative of hyperfibrinolysis. Inhibition of fibrinolysis may promote clotting or thrombosis; more likely due to the presence of DIC When there is uncertainty as to whether the cause of bleeding is primary fibrinolysis or DIC, this distinction must be made before administering Must not be used in the presence of disseminated intravascular coagulation (DIC) without concomitant heparin Rapid intravenous administration of the drug should be avoided since this may induce hypotension, bradycardia, and/or arrhythmia. Do not administer undiluted DIC = Disseminated intravascular coagulation 34 Aminocaproic Acid (Amicar®) Warnings/Precautions (cont.) Do not administered with Factor IX Complex concentrates or Anti- Inhibitor Coagulant concentrates, as the risk of thrombosis may be increased Injection product contains benzyl alcohol as a preservative. The administration of medications containing benzyl alcohol to premature neonates has been associated with a fatal “Gasping Syndrome” Rarely, skeletal muscle weakness with necrosis of muscle fibers has been reported following prolonged administration 35 Aminocaproic Acid (Amicar®) Adverse effects GI (oral): Abdominal pain, diarrhea, nausea, vomiting Musculoskeletal: CPK increased, muscle weakness, myalgia, myopathy Neurologic: Confusion, delirium Thrombosis/Thrombotic complications (rare) Edema Contraindications Disseminated intravascular coagulation (DIC) without the use of heparin Evidence of an intravascular clotting process 36 Tranexamic Acid (Cyklokapron®) Is a synthetic derivative of the amino acid lysine (a lysine analog) that acts as an inhibitor of fibrinolysis Is available as IV or Oral product Oral product is only used for treatment of cyclic menstrual bleeding 37 Tranexamic Acid (Cyklokapron®) Mechanism of action (See picture) Is a competitive inhibitor of lysine binding sites on plasminogen and prevents plasminogen activation (prevents the conversion of plasminogen into the active enzyme plasmin). At much higher concentrations, is a noncompetitive inhibitor of plasmin directly, preventing its binding to fibrin This results in the inhibition of fibrin degradation which allows for the formation of a more stable clot and decreased risk of recurrent bleeding 38 Mechanism of Action of Lysine Analog Anti-Fibrinolytics TXA Fibrin Clot Fibrinolysis Plasminogen Plasmin Tranexamic acid (TXA) binds to lysine binding sites located on plasminogen and PREVENTS the conversion of plasminogen into plasmin and thus decreases the process of fibrinolysis. Fibrin Split Products Tranexamic Acid (Cyklokapron®) Pharmacokinetics Absorption: ~50% (less than that of aminocaproic acid) Distribution Widely distributes throughout extracellular and intracellular compartments of the body of various tissues Rapidly diffused into joint fluid and synovial membranes Metabolism: minimal t1/2 = 2 hours Excretion Renal excretion is the primary route of elimination Is rapidly excreted in the urine and thus must be given IV at short intervals to maintain a therapeutic level Use with caution in renal failure patients due to accumulation 40 Tranexamic Acid (Cyklokapron®) Dosing General dosing range is 1000-2000 mg IVPB over 30 minutes Can be given up to 3-4 times per day depending on indication Do no give faster than 100 mg/min Due to risk of hypotension Do not administer undiluted Dosing is adjusted based on the degree of renal function Several dosing recommendations exist depending on the indication In orthopedic procedures, dosed at 10-20 mg/kg loading dose followed by 1-10 mg/kg/hr continuous infusion In hemophiliacs, 10 mg/kg IV loading dose prior to tooth extraction followed by 10 mg/kg IV 3-4 times per day for 2-8 days 41 Tranexamic Acid (Cyklokapron®) Warnings/Precautions Do not administer without a definite diagnosis of laboratory findings indicative of hyperfibrinolysis. Inhibition of fibrinolysis may promote clotting or thrombosis; this is more likely due to the presence of DIC must not be used in the presence of DIC without concomitant heparin Rapid intravenous administration of the drug should be avoided since this may induce hypotension. Do not administer undiluted Do not administer with Factor IX Complex concentrates or Anti-Inhibitor Coagulant concentrates, as the risk of thrombosis may be increased Visual Defects (color vision changes, visual loss) and retinal venous and arterial occlusions have been rarely reported Send immediately to an ophthalmologist if this occurs Rarely, skeletal muscle weakness with necrosis of muscle fibers has been reported following prolonged administration DIC = Disseminated intravascular coagulation 42 Tranexamic Acid (Cyklokapron®) Adverse effects (IV) GI: nausea, vomiting, diarrhea Blurred vision Convulsions/Seizures (rare) – greater risk with higher doses blocking GABA receptors in the frontal cortex is the suspected mechanism Thrombotic Complications (rare) Includes DVT, PE, cerebral thrombosis, acute renal necrosis, central retinal artery and vein obstruction Hypotension When IV injection is too rapid 43 Tranexamic Acid (Cyklokapron®) Contraindications In patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid in such patients In patients with active intravascular clotting Do not administer with solutions containing penicillin Active or history of thrombosis or thromboembolism Intrinsic risk of thrombosis or thromboembolism (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease, or hypercoagulopathy) 44 45