Glaucoma Drugs.pdf

Lecture 2: Glaucoma Drugs (Ocular Anti-Hypertensives) What is glaucoma: optic neuropathy initially provoked by multifactorial primary mechanisms of damage (PMOD) characterized by ONH Atrophy and secondary induced programmed retinal ganglion cell death causing a characteristic pattern of VF loss. Evi...

Lecture 2: Glaucoma Drugs (Ocular Anti-Hypertensives) What is glaucoma: optic neuropathy initially provoked by multifactorial primary mechanisms of damage (PMOD) characterized by ONH Atrophy and secondary induced programmed retinal ganglion cell death causing a characteristic pattern of VF loss. Evidence-Based Supported PMOD • Elevated intraocular pressure (EIOP) • Decreased Ocular Blood Flow (DOBF) What Causes EIOP? • Two outflow methods • Resistance to Trabecular Aqueous Outflow (TO) o Increased herniation of TM cytoskeleton o Decreased inflammatory signaling to EC Schlemm Canal o Increased Episcleral VP • Resistance to Uveoscleral Aqueous Outflow (USO) o USO Mechanism: Goes back to ciliary body through CB Band, through ciliary muscle bypassing muscle fibers which are restricted by collagen o Too much collagen o Prostaglandin agonists break down collagen between fibers, thus decreasing IOP (Metoproteinate is an enzyme that breaks down collagen fibers) Vascular Concept of OBF • OBF: Ocular Blood Flow • DBP: Diastolic BP • PPa: Perfusion Pressure of Artery • PPv: Perfusion Pressure of Vein • Lean and understand this formula • Refer to slide 7 in scribe notes for more detailed information Factors Involved in DOBF • Decreased DBP/Elevated IOP à Uncompensated DOPP à DOBF (ONH Damage) • Vasculospastic DX/Hyperviscosity Syndrome/EIOP (Migraines) à VA Dysfunction à DOBF (ONH Damage) What about Ocular Biomechanical Properties (OBMP)? • Cornea Viscoelastic Property (way to measure): ability to absorb, energy in absorption • Barriers: protective, rigidity characteristic, hold pressure • Prone to develop Glaucoma in pt with poor ocular biomechanics à poor viscoelastic property Biomechanical Concepts (key terms) • Corneal Hysteresis (CH)- Viscoelasticity o Increase value: better biomechanics and more ability to hold pressure • Corneal Resistance Factor (CRF)- relates to the overall ocular structural rigidity o More rigidity implies a higher IOP • Central Corneal Thickness (CCT)- extrapolated measurement to imply corneal rigidity; viewed as a protective factor • Ocular Response Analyzer (ORA): same principal of air puff tonometer o Will measure the pressure by applanation of the cornea o Resist force of applanation: § Rigid comeback-rigid § Long time comeback: flaccid Factors Involved in Altered OBMP Properties • Decreased CH à Decreased CRF à (two paths) o Decreased CCT à Decreased Corneal Rigidity o Decreased Corneal Rigidity • Decreased Corneal Rigidity à Decreased Protective Factor, Increased Risk Factor Secondary Mechanism of Damage Concept • Elevated IOP/Normal IOP + Mechanical Damage/Ischemic Insult à Optic Neuropathy à Neural Death o Where does neuronal damage come from? § Relation to Neurovascular coupling • Lack of blood flow related to nerve damage • Capillary BF is diminished • Electro-Retinogram measures action potential at different levels in retina • Glutamate Excitotoxicity (diminished glutamate transporter function • NMDA Receptor Activation (excitement): physiological open and close help autonomic flow o Healthy regulation of neurotransmitters in extracellular is key (Glutamate) o In glaucoma it is believed that Glutamate is too much extracellular, the receptor stays open by ligand Magnesium, leading to inflow to cell: Cell death by increase Ca § Re-uptake mechanism when glutamate increases extracellularly and closes to maintain homeostasis • Increases Ca+ Influx • Delayed Calcium deregulation: cell does not have the ability to take Ca+ out of the cell • Nitric Oxide Synthesis • Neurotrophion Depravation • Apoptosis Glaucoma Risk Factors • Elevated IOP • Suspicious Optic Disc o Cupping in relation to disc size o Normal disc size 1.8mm-2.5mm o 0.6/0.6-2.0mm: less risk o 0.4/0.4-1.5mm: more risk • Family History: siblings • Race: primary open angle-black, Hispanics • Increasing Age: 2x the risk • Myopia: long axial length- blood flow has to travel more turning into less blood flow • Diabetes: not really a strong factor • Systemic Vascular Disease: HBP and CRVO • CRVO: Raynaud's disease (decrease blood flow- blue nails and sensitivity to cold) Goals of Pharmacological Medical Therapy • Reduction in the mean IOP to <15 mmHg** o **Actual target is one that stops progression o Has to be stable w no fluctuations • Control of diurnal fluctuation • High rate of response • No Tachyphylaxis (Tachyphylaxis: an acute, sudden drop in response to a drug after its administration) Topical Medication Classes and IOP Lowering Abilities • Prostaglandin Analogues: 6-8 mmHg • Alpha2-Adrenergic Agonists: 2-6 mmHg • Beta Blockers (Adrenergic Antagonists): 3-5 mmHg • Carbonic Anhydrase Inhibitors (CAIs): 2-4 mmHg • CAI/Beta Blocker Combo: 4-6 mmHg • Alpha2-Adrenergic Agonists/Beta Blocker Combo: 4-6 mmHg Prostaglandin Analogues (PGAs) • Travoprost • Bimatoprost (chemically different) • Latanoprost (highly unstable, refrigeration needed) • Tafluprost (not much receptiveness in patients) • PGAs are the first line of medical therapy • Greater efficacy: advise to use at night o More IOP reduction than beta blockers o Flatter diurnal curves vs other therapies o Better response o No tachyphylaxis • Additive to other agents • Good safety • Latanoprost (Xalatan 0.005%) o Mode of therapy: QD PM (refrigerate) o 35% in IOP reduction o Good adjunctive therapy w beta-blockers • Travanoprost (Travatan 0.004%) o Same indications as latanoprost o More stable solution o BAK-Free Travoprost (Travatan Z) § Same formulation, but preserved w SofZia instead of BAK • Bimatoprost (Lumigan 0.01%) o Chemically different o A prostamide o Mode of action § 35% increase in trabecular outflow § 50% increase in uveo-scleral outflow (main mechanism of prostaglandins) • Tafluprost (0.0015%, solution, PF) o Indications: for reducing elevated IOP in patients w open-angle glaucoma or ocular HTN o Clinical Trials: patients w open-angle glaucoma or ocular HTN and baseline IOP of 23-26 mmHg who were treated once daily in the evening demonstrated reductions in IOP at 3 and 6 months of 6-8 mmHg and 5-8 mmHg respectively How do PGAs Work? • Pro-drug: converts to active free fatty acids by corneal enzymes • Binds to FP receptors in ciliary body • Up-regulation of matrix metalloproteinase (MMPs) which degrade extracellular proteins of the ciliary muscle (increase uveo-scleral outflow) o An increase of collagen decreases uveo-scleral outflow o PG2 Receptors secrete prostaglandins (pro-inflammatory) • Also enhances TOP • IOP reductions of 30% • One third of patients achieve reductions of 40-50% Trabecular Outflow MOA • Inflammation always increases permeability • SLT Therapy (same outcome as prostaglandins à Bimatoprost-Lumigan) o Increases permeability of cells by signaling w application of laser o The counter to widely held belief that PGAs work via the uveo-scleral outflow pathway & MMPs o Indicates that PGAs have a direct effect on Schlemm’s canal endothelial cell barrier function and therefore the conventional trabecular meshwork aqueous outflow pathway o Regulates the integrity of the intracellular junctions and the permeability of the barriers formed by SCEs What to look out for when using PGAs • Periorbital absorption causes atrophy of eyelid receptors and periorbital fat cells o Bulb of eyelashes increases w PGA usage o Lashes fall because of increased density (Bimatoprost-Lumigan) • Conjunctival hyperemia • Periorbital hyperpigmentation (racoon eyes) • Anterior Uveitis • CME post-cataract surgery (cystoid macular edema) Ocular Surface Disease and the use of PGAs • Ocular surface disease is common in the glaucoma population (a big reason for noncompliance w meds) • Inflammation of the cornea (treat w AT) PGA Contraindications • Pregnancy: category C, potential benefits may warrant use o Weigh risk vs benefits o History of miscarriage? • Inflammatory conditions: this is a BIG ONE o Chronic Uveitis Sympathomimetics: Alpha Adrenergic Agonists (AAA) • 2nd line after PGA • Activate alpha 2 receptors (alpha 2 is inhibitory to AH production) • Inhibit beta 2 (b-2 increases AH production) • • MOA: reduces aqueous humor production, increase aqueous outflow (uveo-scleral) Indications o Brimonidine (Alphagan P) can be 1st line § Purine breakdown to oxygen and water, shrinking of cells can cause itchiness o Apraclonidine: exhibits tachyphylaxis adjunctive, also short-term adjunctive therapy prior to glaucoma therapy o Pre and Post SX use in IOP spikes to decrease them • Dosage is BID (in conjugation w other meds) or TID • Ocular Side Effects o Allergic Reactions: in the form of folliculitis (you will not see papillae) • Systemic Side Effects o HTN o Dysgeusia (bad taste in mouth) o Anxiety • Contraindications o MAOI Therapy Beta Blockers • MOA: reduce aqueous humor production • Indications: Could be 1st line but also adjunctive • All used BID o Betaxolol (B-1 selective)- does not affect bronchi, blocks Ca channelsà increase in BF to brain o Carteolol: TID, does not cross BBB (no depression) • Timolol (Timoptic) 0.5% • Betaxolol (Betopic-S) 0.25% • Carteolol (Ocupress) 1% • Levobunolol (Betagan) 0.25-0.5% • Metipranolol (OptiPranolol) 0.3% Things to know about Beta Blockers • Have Sulfonic Acid: CI in sulfa allergies • Numbs cornea (pts forget to blink) • Lipophilic • Masking of Hypoglycemic effect • Exasperation of Asthma • CHF • Cross Blood Brain Barrier, decreasing 5-HT à depression Non-Selective Beta Blockers • Timolol Maleate (Timoptic 0.25, 0.5; XE 0.5%, Ocudose PF; Betimol 0.5%) o New mode of therapy- 0.25% QD in the mornings o Maximum effect in 3 weeks o Washout period 1-2 months (time in a clinical trial receive no active medication so that all traces of the drug are washed out of a patient's system) o Liposoluble substance o Cosopt- Dorzolamide (AAA)/timolol • Levobunolol (Betagan 0.25%, 0.5%) o Same indications as Timolol o More effective in some patients o More SE in some patients • Carteolol (Ocupress 1%) o BID o Equally as effective as Timolol o Less effective than Betagan in some patients o Hydrosoluble substance (less side effects/ less risk of heart disease) o Increase the ratio of high density lipids to total cholesterol Cardio-Selective Beta Blockers • Betaxolol (Betoptic-S 0.25% suspension) o Beta-1 blocker (safer in asthmatic patients o BID o Calcium channel blocking activity o Caution in pts w sulfa allergies Beta Blocker Side Effects • Ocular o Corneal anesthesia related to dry eye (patients forget to blink) o Superficial Punctate Keratitis (SPK) • Systemic o CHF Exasperations o Depression • Contraindications o Sinus Bradycardia o CHF in diastolic hemodynamically unstable patients and systolic o Bronchial Asthma o COPD Carbonic Anhydrase Inhibitors • MOA: reduces aqueous production • Indication: adjunctive • Ocular Side Effects: SPK • Sympathetic Side Effects: (Dry mouth & eyes, bitter metallic taste, GI upset bc systemic absorption) • BID or TID • Dorzolamide (Trusopt) 2%: decrease AH Production, BID • Brinzolamide (Azopt) 1%: BID Do we still use Pilocarpine? • Not used in open angle glaucoma, used as a mechanism to prevent acute angle closure • Appositional closure: not impacted in the angle • Pilocarpine is a parasympathomimetic in autonomic NS (involuntary motor system) o Pupil will be miotic by muscarinic receptors on the pupil o Accommodation by constriction of ciliary muscle will increase the outflow of AH § Radial § Circular: involved in accommodation § Longitudinal: not associated w accommodation, but with flow at the scleral spur • Pulling on the scleral spur will open the trabecular meshwork Pilocarpine (Cholinergic) (Pilocar 1%, 2%, 4%, 6%; Ocusert) • Direct acting parasympathomimetic (causes pupil constriction-miosis) • Muscarinic receptor innervation at the sphincter and ciliary muscle • MOA: increase TO, not related to the degree of miosis • QID • Side Effects o Conjunctival Hyperemia o Enhancement of Inflammatory process o Posterior subcapsular cataracts o Bronchial Constriction Benefits of Combination Product Treatment (two drugs in one drop) • Increase compliance- simple dosing schedule • Cost of one medication vs two • Brinzolamide/Brimonidine Tartrate 1%/0.2% suspension • NEW: Alphagan w brinzolamide • Dorzolamide 2% / Timolol 0.5% (Cosopt) • Brimonidine 0.2% / Timolol 0.5% Compliance is a hindrance for treatment • 2 out of every 3 patients admit to missing at least 2 medication treatments per month • Over 40% of patients miss at least 10% of TID or QID doses • 15% of patients miss greater than 50% of doses New Medications • VYZULTA (Latanoprostene bunod ophthalmic solution) 0.024% o Dual MOA: metabolizes into two moieties § Latanoprost Acid à FP receptor à MMPs à Extracellular matrix remodeling § Butanediol Mononitrate (release NO to increase outflow through the TM and Schlemm’s Canal) à Soluble Guanylyl cyclase à cGMP/PKG à TM cell relaxation à increase TM/Schlemm’s Canal outflow • 1st line will be laser one day- Direct Selective Trabeculoplasty (DSLT) What else? • Rhopressa (netasudil) 0.02% solution o Rho Kinase (enzyme involved in herniation of TM) and NE transporter inhibitor (3 activates) o Triple Action o Clinical Trials: QD- lowered IOP by 5.7 mmHg from baseline o Not too accepted in practice Lecture 3: Anticoagulants, Platelet Aggregation Inhibitors, and Thrombolytics Anemia: hematologic disease as a result of low hemoglobin concentration • Etiologies o Decrease formation of RBCs o Decrease Hb concentrations o Chronic blood loss o Hemolysis o Bone marrow abnormalities o Malignancies o Nutritional deficiency § During Pregnancy (vit B-12 deficiency) § During Lactation • Rule out vitamin b-12 deficiency before treatment Iron Deficiency Anemia (most common nutritional deficiency) • Due to a negative Fe++ balance as a consequence of deficiency or inadequate states • Fe++ is stored in intestinal mucosal cells as ferritin until needed • States of Deficiency o Acute or chronic blood loss o Increase demand as in accelerated growth o Heavy mensural pregnancy o Microscopically hypochromic microcytic anemia • RX: Oral Fe++ Supplement as Ferrous Sulfate (produces constipation) (old exam question, pick two: advise pregnant women w anemia: ferrous sulfate and foliate acid) Folic Acid Deficiency • Etiologies o Increase demand during pregnancy and lactation o Poor absorption o Alcoholism o Treatment w dihydrofolate reeducates inhibitors such as methotrexate and trimethoprim • RX: Folic acid supplements Cyanocobalamin Vit B-12 Pernicious Anemia • Deficiency due to low dietary levels or poor absorption (no production if intrinsic factor) o Intrinsic Factor: a glycoprotein produced by the parietal cells located at the gastric body and fundus. Intrinsic factor plays a crucial role in the transportation and absorption of the vital micronutrient vitamin B12 by the terminal ileum. • Formulations o Oral Intranasal Parenteral • Erythropoietin: hormone that stimulates production of RBC o A glycoprotein, kidney hormone which stimulate erythropoiesis o Recombinant technology has made it possible to administrate more readily (parenteral) o Application § End stage renal disease malignancies § HIV+ subjects o Patients w kidney failure § This agent isn’t produced adequately and leads to something similar to iron deficiency § Pts can benefit by giving this protein via parenteral admin • Improves manifestation of anemia • Give additional doses afterward for maintenance • Hydroxyurea (cancer drug) o Chronic Myelogenous Leukemia (CML) o Polycythemia vera (PV) o In sickle cell anemia (HbS disease) apparently increases the concentration of fetal hemoglobin (HbF) diluting the concentration of HbS Hemostasis (requires two different structures, proteins that are inactivates and platelets) • Normal healthy tissue o Hemostasis maintains a balance and blocks unwanted activation of clot formation o Healthy intact endothelium releases prostacyclin o Prostacyclin binds to platelet membrane receptors cAMP o cAMP stabilizes inactive GP IIb/IIa receptors Inhibiting degranulation • Platelets o Discoid cytoplasmic fragments from megakaryocytes o Circulate in the blood and are essential for clot formation and hemostasis • Thrombus o Pathologic formation of an outward clot w/in a blood vessel or the heart • Emboli o Thrombus which floats within the blood (arterial and venous) Clot Formation • Essential components o Dependent on platelet number and adequate function o Together, with the proper activation of the coagulation cascade for its stabilization • Begins w platelet activation o This process involves 3 steps: adhesion, degranulation, aggregation Platelet Aggregators (old exam questions) • Exposed collagen-most important • ADP released during platelet activation (also releases thromboxane A2 which promotes further aggregation) • Decrease concentration of prostacyclin • Thromboxane (produced during Arachidonic Acid catabolism by cyclooxygenase) • Exposure of platelet fibrin receptors Do not take ibuprofen with blood thinners Platelet Aggregator Inhibitors • Agents are used in prevention and treatment of cardiovascular disease & maintenance of vascular grafts • Aspirin o Irreversibly inhibits the cyclogeneses pathway of Arachidonic Acid (suppressing Thromboxane A2) o Effect lasts 7-10 days (old exam question) o Should use a loading dose followed by smaller maintenance doses • Dipyridamole o Coronary vasodilator, used prophylactically in CAD (angina) o Works by increasing cAMP levels which decrease formation of Thromboxane A2 o Effective in combination with warfarin preventing embolization in prosthetic heart valves o Used in CAD, reduces incidence of ischemic events/MI o MOA: suppress thromboxane A2 • Ticlopidine and Clopidogrel o Inhibits platelet aggregation by blocking ADP pathway (old exam question) involved in binding platelets to fibrinogen • • o Useful in preventing CVA, CVD, PVD o Used in stent insertion o Adverse Effects: neutropenia (old exam question), inhibition of CYP-450 Abciximab o Monoclonal antibody against GpIIb/IIa complex, blocking the binding of factors I and X, blocking platelet aggregation o Used for short term effects o Used IV and effects persist for 24-48 hours o Adverse Effects: bleeding Eptifibatide and Tirofiban o Similar in action and therapeutic use to Abciximab o Less side effects Anticoagulants • Heparin o Vitamin K antagonist o Rapid onset of action, indirectly binding to antithrombin III (heparin cofactor) which inhibits activation of several clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa) o Use SC or IV, NEVER IM (could cause hematoma w IM admin) o Clinical Use § DVT § PE § Extracorporeal devices o Choice of anticoagulation during pregnancy (doesn’t cross the placenta) o IV use as bolus or slow continuous infusion for 7-10 days o Dose should be titrated to maintain PTT 1.5-2.5 its control time, INR o Metabolized in the Liver o Excreted by the kidney o Disorders effecting the liver or kidney increase the half-life o Adverse Effects § Hemorrhage (resolved by discontinuation or administration of protamine sulfate in emergency situations) § Hypersensitivity (obtained from animal sources): thrombocytopenia § Contraindications • Bleeding disorder • Hypersensitivity • Post operative stages (eye, brain, or spinal cord) • Warfarin (rat poison) o Anticoagulant which antagonizes the function of Vitamin K (factors 3, 5, 8, 9, and 10) o Action observed 8-12 hours after administration o 99% bound to albumin (may be displaced by other drugs with elevation of half-life) o CI in pregnancy bc it crosses the placenta and is teratogenic o Follow up: PT 1.5-2.5 its control time, INR o Adverse Effects § Hemorrhage § Minor bleeding treated by discontinuation, and administration of Vit. K • Severe bleeding requires a greater dose of Vit. K • Fresh frozen Plasma • Specific blood factors Interactions § Inhibit metabolism and increase concentration in blood • Acute Alcohol, Cimetidine, Chloramphenicol, Cotrimoxazole, Metronidazole, Phenylbutazone § Increase metabolism and decrease concentration in blood • Chronic Alcohol, Barbiturates, Glutethimide, Griseofulvin, Rifampin Other Parenteral Anticoagulants (thrombin antagonists) • Lepirudin o Thrombin antagonist w little or no activity on platelet function o Half-life: 1 hour o Mostly eliminated by urine o Side effects: bleeding o Follow Up: renal function, and aPTT, INR • Argatroban o Thrombin inhibitor o Used prophylactically in heparin induced thrombocytopenia (HIT) (old exam question) o Side effects: bleeding o Follow Up: aPTT, INR • Fondaparinux o Purely synthetic pentasaccharide o Approved for DVT in orthopedic surgery of hip and knee o Binds to factor Xa o Contraindicated in Renal Impairment o May be used in HIT Thrombolytic Agents • Alteplase (tPA)-ACTIVASE • Reteplase- RETAVASE • Streptokinase • Tenecteplase- TNKASE • Urokinase- KINLYTIC • MOA: act directly to convert plasminogen to plasmin which cleaves fibrin (lysing a thrombi) • Dissolution and reperfusion (dissolution of blood clot) occurs w high frequency when therapy is instituted early after clot formation. But may lead to further clot formation • Therapeutic use o Originally indicated for DVT and acute PE, now has extended to Acute MI o Window period of 2-6 hours for myocardial salvage in Acute Cerebral Ischemia (CVA) o Peripheral arterial thrombus o Un-clotting catheters and shunts • Adverse effects o Hemorrhage o Decreased wound healing • Contraindications (old exam question, what isn’t a contraindication? Catheter) o HX of CVA o Pregnancy o Metastatic Carcinoma • Profile (old exam question) o Antigenicity: Streptokinase is highest o o Fibrin Specificity (coupling w fibrin vs free fibrinogen): Alteplase and Urokinase are highest o Half-Life: Streptokinase is highest • Alterplase (tPA) (tissue plasminogen activator) o Serine protease obtained from recombinant DNA o At low levels, couples specifically w fibrin in a thrombus (fibrin selective) (old exam question) and not on free fibrinogen o Unfortunately, at therapeutic doses, may activate circulating plasminogen related w hemorrhages o Clinical Use § Acute myocardial infarction § PE § Acute ischemic infarct (CVA) (if given prior to 3 hours of onset improves outcome and ability to perform daily activities) o Pharmacokinetics § Very short half-life (>5 min) § Use in a bolus of 100 mg (10 mg. STAT followed by slow infusion in 90 min) • Streptokinase o Has no enzymatic activity but couples 1:1 with plasminogen converting it into its active state o Also catalyze degradation of fibrinogen and state factors V and VII o Clinical use § Acute MI § DVT § Acute PE § Arterial Embolism § Occluded access shunts o Pharmacokinetics § MI: given IV constant infusion for 1 hour § Thromboplastin time is maintained 2 to 5 times its control (afterwards patient is continued on anticoagulation) § Aminocaproic acid is used to counteract life threatening bleeding o Side Effects § Bleeding § Hypersensitivity 3% of pts: since it’s a foreign protein (Strp. B-hemol.) allergic reactions may occur even anaphylaxis • Anti-Streptococcal Ab may combine w drug, diminishing its efficiency • Anistreplase (anysolated plasminogen streptokinase) o Modified streptokinase molecule semiselective for clot site since it binds to only fibrin o Half-life: 90 minutes o Given for 2-5 minutes Drugs used for stopping bleeding • Specific procoagulant factors deficiency lyophilized (F VIII) (Hemophilia) • Fresh Frozen Plasma (FFP) for immediate hemostasis (contains all coagulation factors) (old exam question) • Aminocaproic Acid o Synthetic agent that inhibits plasminogen activation o Complication: intravascular thrombus • Protamine Sulfate o Antagonize anticoagulant effect of heparin o Side Effects: hypersensitivity, dyspnea, bradycardia, and hypotension when given IV rapidly • Vitamin K o May stop bleeding 2ndary to oral anticoagulants (slow response >24 hours) • Apoprotein o Serine proteases inhibitor blocks plasmin o Prophylactic use to reduce perioperative blood loss (before sx) Antidotes for Bleeding • Aminocaproic Acid & Tranexamic Acid à Fibrinolytic State • Protamine sulfate à heparin • Vitamin K1 à Warfarin