Pharmacology Exam 3.docx

Pharmacology 2 Exam 3 Lecture 1: Antihypertensive Agents Blood Pressure Classification Normal: <120 and <80 Prehypertension: 120-139 or 80-89 Hypertension: >140/90 Stage 1: 140-159 or 90-99 Stage 2: >160 or >100 Essential Hypertension 90-95% of HTN cases, the cause isn’t known Sy...

Pharmacology 2 Exam 3 Lecture 1: Antihypertensive Agents Blood Pressure Classification Normal: <120 and <80 Prehypertension: 120-139 or 80-89 Hypertension: >140/90 Stage 1: 140-159 or 90-99 Stage 2: >160 or >100 Essential Hypertension 90-95% of HTN cases, the cause isn’t known Symptomatic treatment, reduce BP No true cure yet Known Causes of Secondary Hypertension Sleep Apnea CKD Primary aldosteronism (Conn’s Syndrome) (Increase absorption of Na+, Decrease absorption of K+) Renovascular disease Chronic steroid therapy and Cushing’s Syndrome Pheochromocytoma Coarctation of the aorta (congenital narrowing) Thyroid or parathyroid disease (too high production of hormones) Prevalence More prevalent in men Highest prevalence in elderly African-American females Complications Cardiovascular System CNS (strokes) Renal System Retinal Damage Organ Damage Heart Left ventricular hypertrophy (over-growth) Coronary artery disease Myocardial infarcts Heart failure Brain Stroke or TIA Risk Factors Obesity (big risk) Stress (type A personalities) Lack of exercise Diet (excess dietary salt) Alcohol intake/Cigarette smoking Most Important Peripheral Organ for BP: Kidney/Adrenal Gland BP Goals <140/<90 and lower if tolerated <130/<80 in diabetics <130/<85 in cardiac failure <130/<85 in renal failure <125/<75 in renal failure w/ proteinuria > 1.0g/24 hours Lifestyle Modifications Reduce weight to normal BMI: 5-20mmHg/10kg loss DASH (Dietary Approaches to Stop Hypertension): 8-14 mmHg, Emphasizes fruits, veg, low fat dairy foods, and reduce sodium intake Dietary Sodium Reduction: 2-8 mmHg Increase Physical activity: 4-9 mmHg Reduce alcohol consumption: 2-4 mmHg Initial Drug Choices With Compelling Indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) Without Compelling Indications Stage 1 Hypertension: Thiazide-type diuretics for most May consider ACEI, ARB, BB, CCB, or combination Stage II Hypertension: 2-drug combo for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Mean Arterial Pressure MAP=DP + 1/3(SP-DP) SP=CO=HR*SV DP=SVR Diuretics Used alone or in combination w drugs from other groups Can be used as initial TX Adverse effects: renin secretion due to volume and Na Depletion Thiazides: chlorothiazide, hydrochlorothiazide Loop Diuretics: furosemide, bumetanide, ethacrynic acid Potassium sparing diuretics: spironolactone, triamterene, amiloride Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Diuretics have been as effective as other agents in the prevention of cardiovascular complications associated to HTN Diuretics enhance the efficacy of other agents in multidrug regimens They are cost effective Agents that Inhibit Adrenergic Transmission Reserpine Mechanism: depletes NRTM (NE, DA, 5HT) in the storage vesicle of the central and peripheral nerve endings Main effects: depress NE function centrally and peripherally decreases HR, contractility, and PVR (causes vasodilation due to suppression of NE) Also used as an antipsychotic (stops Dopamine dumping) Adverse Effects: depression, orthostatic hypotension (changes in pressure due to posture, standing drops BP), dry mouth, impotence Pharmacokinetics: onset is slow, gradient effect (not used for emergencies bc slow) Rarely use for HTN Guanethidine Mechanism: depletes the nerve ending of the NE in the PNS (peripherally and only nerves w NE) Main Effect: Decrease in PVR and decrease in HR decrease in BP Adverse effects: orthostatic hypotension, Na+ and water retention (bc vasodilation); no CNS effects (causes depletion but there is an initial surge of NE, can cause cardio problems) Pharmacokinetics: Poorly absorbed from the GI, onset is slow (1-2 weeks). Metabolites excreted in urine Not used anymore because of the severe side effects Selective Alpha-1 Adrenergic Receptor Blockers Prazosin-Minipress, Terazosin-Hytrin (used for BPH-Benign Prostate Hyperplasia), Doxazosin-Cardura Favorable influence on serum lipid levels and no interference with glucose metabolism Mechanism: block alpha1 receptors in vasculature (BPH: arteriolar vasodilation) (blocks innervation of NE and their receptors so bladder sphincter gets loose so patient can pee) Main effects: decrease PVR decrease BP Adverse effects: 1st dose phenomenon (dramatic pressure drop), fluid retention (edema), dizziness, headache Pharmacokinetics: t1/2=4.5 hours Used in stage 1 and stage 2 HTN in combo regimen Beta-Adrenergic Blocking Agents Classification Nonselective (1st generation) (some w intrinsic sympathomimetic activity (ISA)) ISA: b-1 activated at heart, accelerate HR, blocking causes decrease HR. b-2 causes vasodilation in peripheral arteries, and bronchodilation in the lungs, blocking them causes constriction in peripheral arteries and bronchi. Asthmatic & diabetic patients may be a bad idea for these patients. Mask hypoglycemic effects that insulin causes in diabetics. Cardio-selective (b-1 selective, 2nd generation) Hybrid antihypertensive drugs (Beta and Alpha blocking CV actions) (3rd generation) Proposed Mechanisms Block cardiac beta1 receptors lower HR lower CO Block renal beta1 receptors low renin, lower PVR (at level of kidneys causes lower production of renin, causing constriction) Oppose action of NE Released (ISA) (releases, but opposes what it releases) 1st Generation Non-Selective Propranolol Timolol (hydrophilic) Pindolol* Penbutolol* Carteolol* 2nd Generation B1-Selective (good for diabetics and asthmatics) Metoprolol Acebutolol* Atenolol (hydrophilic) Betaxolol Bisoprolol 3rd Generation (Hybrids) Labetalol (alpha and beta*) (used in emergency rooms to lower BP in hypertensive crisis) Carvedilol (alpha and beta) (blocker of choice for CHF, decrease HR and PVR) Propranolol (Inderal) Mechanism Block cardiac B-1 Receptors lower CO Block renal B1 Receptors lower renin, lower PVR Main effects: decrease HR and PVR Adverse effects: bradycardia, mental depression (decreases 5HT levels), B2 blockade in airways, glucose and lipid metabolism, vasoconstriction in extremities Pharmacokinetics: 30-50% metabolized in the first pass in the liver. T1/2 3-5 hours, slow release (extended release) available Uses: used in stage 1 and 2 HTN alone, or in combination Drug Interactions: (be cautious w other meds that slow the heart) verapamil (angina medication), diltiazem, digitalis (these cause AV block) Labetalol (Trandate) A combined alpha-1, beta-1, and beta-2 blocker. Beta blocking action is more prominent Also has ISA property Can be given IV for hypertensive emergencies Carvedilol (Coreg) Nonselective beta blocker and alpha 1-blocker BB choice in the treatment of CHF Agents that act on the CNS a-Methyldopa (Aldomet), clonidine (Catapres) (ER) Mechanism: central alpha-2 agonist in brain (alpha-2’s are inhibitory) (agonist effect inhibits system), suppress sympathetic adrenergic activity Main effect: decrease PVR and HR Adverse effects: sedation, drowsiness, dry mouth, impotence, bradycardia; false (+) Coombs’ antiglobulin test (measures antibodies against RBC, hemolytic anemia) Pharmacokinetics: oral or parenteral, transdermal; T1/2=2hr Used for stage 1 and 2 HTN Vasodilator Drugs Calcium entry blockers (nifedipine and others) Potassium channel openers (minoxidil, diazoxide iv) Direct acting vasodilators (hydralazine, Na-nitroprusside iv) Common adverse effects due to fall in BP: Reflex tachycardia (caused by excess dilation) Elevate reninNa/H2O retention (aldosterone and angiotensin cause pressure and retention) Calcium Channel Blocker Mechanism: inhibit Ca entry through L-type voltage gated channels (L-type cause a surge for action potentials) Non-Dihydropyridines Act primarily on the heart (vasodilation and decrease HR) Phenylalkylamines: verapamil- negative inotropic/chronotropic and coronary vasodilatory effect Benzothiazepines: diltiazem- negative chronotropic and coronary and peripheral vasodilatory effect (mild, periphery) Dihydropyridines (DHP) Nifedipine, amlodipine Act on peripheral vascular system (vasodilation) May cause reflex tachycardia Ankle edema (peripheral edema) Nifedipine (DHP) Mechanism: selective blockade of vascular Ca channels Main effect: vasodilation lower PVR Lower BP Adverse effects: headaches, ankle edema, dizziness, reflex tachycardia with short acting version (now have Procardia SR) Use: Hypertension (more effective in African-Americans), angina Not effective as an antiarrhythmic drug Verapamil and Diltiazem (N-DHP) Mechanism: blockade of Ca channels in Heart muscle and the AV node (pitstop for electrical conduction) Vasculature (diltiazem) Main effects: decrease HR and HC decrease CO and coronary vasodilatory; decrease PVR (diltiazem) Adverse effects: similar to DHP but NO Reflex Tachycardia Drug interaction: caution for AV block w beta blockers, and digitalis (cardio glycosides-negative inotropic effect) Uses: HTN, Angina, Arrhythmias Potassium Channel Openers Minoxidil (Loniten), Diazoxide (Hyperstat IV, Pinacidil) Mechanism: open K-channels of vascular smooth muscle cells K-efflux hyperpolarization vasodilation Main Effect: vasodilation lower PVR lower BP Adverse effects: reflex tachycardia, Na and fluid retention; hyperuricemia, hyperglycemia (Diazoxide) Uses: Diazoxide IV in hypertensive emergencies Direct Acting Vasodilators Na-nitroprusside IV (Nipride) Mechanism: metabolite is nitric oxide cGMP. NO is rapid acting venous and arteriolar vasodilator Main effect: vasodilation lower PVR lower BP Adverse Effects: reflex tachycardia, severe Hypotension, possible cyanide poisoning Pharmacokinetics: rapid acting, short plasma half life Use: hypertensive emergencies Agents that Affect RAAS ACE Inhibitors: captopril, enalapril, lisinopril Angiotensin II receptor blockers (ARB): losartan, valsartan, irbesartan RAAS Maintenance System of kidney, controls BP Angiotensinogen- produced in liver, goes into blood. When exposed to renin at the liver, it converts to Angiotensin I. ACE (angiotensin converting enzyme-produced in the lungs and kidneys): converts angiotensin I to angiotensin II Angiotensin II: vasoactive substance, several activities Increases sympathetic activity leading to vasoconstriction Causes reabsorption of Na and Cl, excretion of potassium, and H2O retention in the tubular area Water follows sodium Excites the adrenal gland cortex producing aldosterone (causes reabsorption of sodium and excretion of potassium) Activation of the pituitary gland, causing excretion of ACTH which activates ADH (anti-diuretic hormone) which decreases urination Signaling of too much vasodilation activates renin secretion ACE Inhibitors Captopril (Capoten), Enalapril (Vasotec), Lisinopril (Prinivil), Ramipril (Altace) No adverse effects on the plasma lipids, glucose, or sexual function Drug class of choice in diabetes-related early-stage proteinuria (excessive protein in urine) Contraindicated in pregnancy Not as effective in African Americans Mechanism: inhibit ACE low circulating Ang II (acts on ang I) decrease PVR Main Effects: decreased PVR decreased BP Adverse effects: skin rash, taste, cough, hyperkalemia (too much potassium in system) Pharmacokinetics: half-life= 3, 11, 12 respectively Use: stage 1 and 2 HTN; CHF Angiotensin II receptor blockers (ARB) Losartan-Coozar, Valsartan-Diovan, Irbesartan-Avapro, Candesartan-Atacand Mechanism: selectively block Ang II AT-1 receptor decrease PVR decrease BP Adverse effects: no cough, very few adverse similar to ACE inhibitors 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) Increased herniation of TM cytoskeleton Decreased inflammatory signaling to EC Schlemm Canal Increased Episcleral VP Resistance to Uveoscleral Aqueous Outflow (USO) USO Mechanism: Goes back to ciliary body through CB Band, through ciliary muscle bypassing muscle fibers which are restricted by collagen Too much collagen 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 Uncompensated DOPP DOBF (ONH Damage) Vasculospastic DX/Hyperviscosity Syndrome/EIOP (Migraines) VA Dysfunction 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 poor viscoelastic property Biomechanical Concepts (key terms) Corneal Hysteresis (CH)- Viscoelasticity Increase value: better biomechanics and more ability to hold pressure Corneal Resistance Factor (CRF)- relates to the overall ocular structural rigidity 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 Will measure the pressure by applanation of the cornea Resist force of applanation: Rigid comeback-rigid Long time comeback: flaccid Factors Involved in Altered OBMP Properties Decreased CH Decreased CRF (two paths) Decreased CCT Decreased Corneal Rigidity Decreased Corneal Rigidity Decreased Corneal Rigidity Decreased Protective Factor, Increased Risk Factor Secondary Mechanism of Damage Concept Elevated IOP/Normal IOP + Mechanical Damage/Ischemic Insult Optic Neuropathy Neural Death 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 Healthy regulation of neurotransmitters in extracellular is key (Glutamate) 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 Cupping in relation to disc size Normal disc size 1.8mm-2.5mm 0.6/0.6-2.0mm: less risk 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** **Actual target is one that stops progression 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 More IOP reduction than beta blockers Flatter diurnal curves vs other therapies Better response No tachyphylaxis Additive to other agents Good safety Latanoprost (Xalatan 0.005%) Mode of therapy: QD PM (refrigerate) 35% in IOP reduction Good adjunctive therapy w beta-blockers Travanoprost (Travatan 0.004%) Same indications as latanoprost More stable solution BAK-Free Travoprost (Travatan Z) Same formulation, but preserved w SofZia instead of BAK Bimatoprost (Lumigan 0.01%) Chemically different A prostamide Mode of action 35% increase in trabecular outflow 50% increase in uveo-scleral outflow (main mechanism of prostaglandins) Tafluprost (0.0015%, solution, PF) Indications: for reducing elevated IOP in patients w open-angle glaucoma or ocular HTN 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) An increase of collagen decreases uveo-scleral outflow 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 Bimatoprost-Lumigan) Increases permeability of cells by signaling w application of laser The counter to widely held belief that PGAs work via the uveo-scleral outflow pathway & MMPs Indicates that PGAs have a direct effect on Schlemm’s canal endothelial cell barrier function and therefore the conventional trabecular meshwork aqueous outflow pathway 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 Bulb of eyelashes increases w PGA usage 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 Weigh risk vs benefits History of miscarriage? Inflammatory conditions: this is a BIG ONE 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 Brimonidine (Alphagan P) can be 1st line Purine breakdown to oxygen and water, shrinking of cells can cause itchiness Apraclonidine: exhibits tachyphylaxis adjunctive, also short-term adjunctive therapy prior to glaucoma therapy Pre and Post SX use in IOP spikes to decrease them Dosage is BID (in conjugation w other meds) or TID Ocular Side Effects Allergic Reactions: in the form of folliculitis (you will not see papillae) Systemic Side Effects HTN Dysgeusia (bad taste in mouth) Anxiety Contraindications MAOI Therapy Beta Blockers MOA: reduce aqueous humor production Indications: Could be 1st line but also adjunctive All used BID Betaxolol (B-1 selective)- does not affect bronchi, blocks Ca channels increase in BF to brain 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 depression Non-Selective Beta Blockers Timolol Maleate (Timoptic 0.25, 0.5; XE 0.5%, Ocudose PF; Betimol 0.5%) New mode of therapy- 0.25% QD in the mornings Maximum effect in 3 weeks 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) Liposoluble substance Cosopt- Dorzolamide (AAA)/timolol Levobunolol (Betagan 0.25%, 0.5%) Same indications as Timolol More effective in some patients More SE in some patients Carteolol (Ocupress 1%) BID Equally as effective as Timolol Less effective than Betagan in some patients Hydrosoluble substance (less side effects/ less risk of heart disease) Increase the ratio of high density lipids to total cholesterol Cardio-Selective Beta Blockers Betaxolol (Betoptic-S 0.25% suspension) Beta-1 blocker (safer in asthmatic patients BID Calcium channel blocking activity Caution in pts w sulfa allergies Beta Blocker Side Effects Ocular Corneal anesthesia related to dry eye (patients forget to blink) Superficial Punctate Keratitis (SPK) Systemic CHF Exasperations Depression Contraindications Sinus Bradycardia CHF in diastolic hemodynamically unstable patients and systolic Bronchial Asthma 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) Pupil will be miotic by muscarinic receptors on the pupil 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 Conjunctival Hyperemia Enhancement of Inflammatory process Posterior subcapsular cataracts 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% Dual MOA: metabolizes into two moieties Latanoprost Acid FP receptor MMPs Extracellular matrix remodeling Butanediol Mononitrate (release NO to increase outflow through the TM and Schlemm’s Canal) Soluble Guanylyl cyclase cGMP/PKG TM cell relaxation increase TM/Schlemm’s Canal outflow 1st line will be laser one day- Direct Selective Trabeculoplasty (DSLT) What else? Rhopressa (netasudil) 0.02% solution Rho Kinase (enzyme involved in herniation of TM) and NE transporter inhibitor (3 activates) Triple Action Clinical Trials: QD- lowered IOP by 5.7 mmHg from baseline Not too accepted in practice Lecture 3: Anticoagulants, Platelet Aggregation Inhibitors, and Thrombolytics Anemia: hematologic disease as a result of low hemoglobin concentration Etiologies Decrease formation of RBCs Decrease Hb concentrations Chronic blood loss Hemolysis Bone marrow abnormalities Malignancies 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 Acute or chronic blood loss Increase demand as in accelerated growth Heavy mensural pregnancy 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 Increase demand during pregnancy and lactation Poor absorption Alcoholism 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) 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 Oral Intranasal Parenteral Erythropoietin: hormone that stimulates production of RBC A glycoprotein, kidney hormone which stimulate erythropoiesis Recombinant technology has made it possible to administrate more readily (parenteral) Application End stage renal disease malignancies HIV+ subjects 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) Chronic Myelogenous Leukemia (CML) Polycythemia vera (PV) 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 Hemostasis maintains a balance and blocks unwanted activation of clot formation Healthy intact endothelium releases prostacyclin Prostacyclin binds to platelet membrane receptors cAMP cAMP stabilizes inactive GP IIb/IIa receptors Inhibiting degranulation Platelets Discoid cytoplasmic fragments from megakaryocytes Circulate in the blood and are essential for clot formation and hemostasis Thrombus Pathologic formation of an outward clot w/in a blood vessel or the heart Emboli Thrombus which floats within the blood (arterial and venous) Clot Formation Essential components Dependent on platelet number and adequate function Together, with the proper activation of the coagulation cascade for its stabilization Begins w platelet activation 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 Irreversibly inhibits the cyclogeneses pathway of Arachidonic Acid (suppressing Thromboxane A2) Effect lasts 7-10 days (old exam question) Should use a loading dose followed by smaller maintenance doses Dipyridamole Coronary vasodilator, used prophylactically in CAD (angina) Works by increasing cAMP levels which decrease formation of Thromboxane A2 Effective in combination with warfarin preventing embolization in prosthetic heart valves Used in CAD, reduces incidence of ischemic events/MI MOA: suppress thromboxane A2 Ticlopidine and Clopidogrel Inhibits platelet aggregation by blocking ADP pathway (old exam question) involved in binding platelets to fibrinogen Useful in preventing CVA, CVD, PVD Used in stent insertion Adverse Effects: neutropenia (old exam question), inhibition of CYP-450 Abciximab Monoclonal antibody against GpIIb/IIa complex, blocking the binding of factors I and X, blocking platelet aggregation Used for short term effects Used IV and effects persist for 24-48 hours Adverse Effects: bleeding Eptifibatide and Tirofiban Similar in action and therapeutic use to Abciximab Less side effects Anticoagulants Heparin Vitamin K antagonist Rapid onset of action, indirectly binding to antithrombin III (heparin cofactor) which inhibits activation of several clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa) Use SC or IV, NEVER IM (could cause hematoma w IM admin) Clinical Use DVT PE Extracorporeal devices Choice of anticoagulation during pregnancy (doesn’t cross the placenta) IV use as bolus or slow continuous infusion for 7-10 days Dose should be titrated to maintain PTT 1.5-2.5 its control time, INR Metabolized in the Liver Excreted by the kidney Disorders effecting the liver or kidney increase the half-life 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) Anticoagulant which antagonizes the function of Vitamin K (factors 3, 5, 8, 9, and 10) Action observed 8-12 hours after administration 99% bound to albumin (may be displaced by other drugs with elevation of half-life) CI in pregnancy bc it crosses the placenta and is teratogenic Follow up: PT 1.5-2.5 its control time, INR 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 Thrombin antagonist w little or no activity on platelet function Half-life: 1 hour Mostly eliminated by urine Side effects: bleeding Follow Up: renal function, and aPTT, INR Argatroban Thrombin inhibitor Used prophylactically in heparin induced thrombocytopenia (HIT) (old exam question) Side effects: bleeding Follow Up: aPTT, INR Fondaparinux Purely synthetic pentasaccharide Approved for DVT in orthopedic surgery of hip and knee Binds to factor Xa Contraindicated in Renal Impairment 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 Originally indicated for DVT and acute PE, now has extended to Acute MI Window period of 2-6 hours for myocardial salvage in Acute Cerebral Ischemia (CVA) Peripheral arterial thrombus Un-clotting catheters and shunts Adverse effects Hemorrhage Decreased wound healing Contraindications (old exam question, what isn’t a contraindication? Catheter) HX of CVA Pregnancy Metastatic Carcinoma Profile (old exam question) Antigenicity: Streptokinase is highest Fibrin Specificity (coupling w fibrin vs free fibrinogen): Alteplase and Urokinase are highest Half-Life: Streptokinase is highest Alterplase (tPA) (tissue plasminogen activator) Serine protease obtained from recombinant DNA At low levels, couples specifically w fibrin in a thrombus (fibrin selective) (old exam question) and not on free fibrinogen Unfortunately, at therapeutic doses, may activate circulating plasminogen related w hemorrhages 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) 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 Has no enzymatic activity but couples 1:1 with plasminogen converting it into its active state Also catalyze degradation of fibrinogen and state factors V and VII Clinical use Acute MI DVT Acute PE Arterial Embolism Occluded access shunts 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 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) Modified streptokinase molecule semiselective for clot site since it binds to only fibrin Half-life: 90 minutes 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 Synthetic agent that inhibits plasminogen activation Complication: intravascular thrombus Protamine Sulfate Antagonize anticoagulant effect of heparin Side Effects: hypersensitivity, dyspnea, bradycardia, and hypotension when given IV rapidly Vitamin K May stop bleeding 2ndary to oral anticoagulants (slow response >24 hours) Apoprotein Serine proteases inhibitor blocks plasmin Prophylactic use to reduce perioperative blood loss (before sx) Antidotes for Bleeding Aminocaproic Acid & Tranexamic Acid Fibrinolytic State Protamine sulfate heparin Vitamin K1 Warfarin Lecture 4: Antihyperlipidemic, Glycemic, & Thyroid Drugs Antihyperlipidemic Drugs Hyperlipidemias Primary Single gene defect Combination of genetic and environmental factors Secondary (acquired) Generalized metabolic disorder DM ETOH (alcohol use) Hypothyroidism Primary biliary cirrhosis Classification Type I: Familial hyperchylomicronemia Type IIa: Familial hypercholesterolemia Type IIb: Familial combined (mixed) hyperlipidemia Type III: Familial dysbetalipoproteinemia Type IV: Familial hypertriglyceridemia Type V: Familial mixed hypertriglyceridemia Goals of Treatment Decrease the production of lipoproteins Increase the catabolism of lipoproteins Increase the removal of cholesterol Treatment leads into a decline in the progression of plaques and regression of preexisting lesions Desired Levels Cholesterol: below 200 mg/dl LDL “bad”: below 130 mg/dl HDL “good”: higher than 60 mg/dl Nicotinic Acid- Niacin (Vitamin B-3) MOA: inhibits a hormone-sensitive lipase in adipose tissue which reduces its breakdown Results in a decreases in: Fatty Acids, Triglycerides, VLDL synthesis (liver), LDL synthesis, cholesterol Results in an increase in HDL Promotes plasminogen secretion Lowers plasma fibrinogen Broadest lipid lowering drug Most potent agent for raising HDL Therapeutic uses: effectively lowers cholesterol and triglycerides Side effects limits its use Intense cutaneous flush, pruritus, and feeling of warmth (attenuated w the use of asprin) Nausea, abdominal pain Predisposition to hyperuricemia and gout Impairs glucose tolerance Hepatotoxic HMG-CoA Inhibitors (“STATINS”) (hydroxy-methyl-glutaryl Coenzyme A) Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, and Rosuvastatin Competitive inhibitors of the first committed step of sterol synthesis (HMG-CoA reductase) Rate limiting step in cholesterol synthesis Inhibit de Novo cholesterol depleting its intracellular supply Therapeutic use: effectively lowers plasma cholesterol in all types of hyperlipidemias Side Effects Hepatotoxic Rhabdomyolysis CI in pregnancy, and children Fibrates Fenofibrate and Gemfibrozil MOA: mediated by gene expression, decreased triglycerides by increasing expression of lipoprotein lipase and decreasing apo C II concentration Stimulates lipoprotein lipase (hydrolyzes triglycerides into chylomicrons and VLDL promoting their removal from the plasma) Indirectly HDL levels increase moderately Decrease plasma fibrinogen Therapeutic use Particularly useful in Type III May be used in Type IV and V when diet or other drugs have failed Pharmacokinetics Well absorbed orally Strongly binds to albumin Excreted in urine as glucuronide conjugate Adverse Effects GI disturbances Formation of gallstones Malignancies (specifically clofibrate) Myositis: immune system attacks your muscles Drug Interactions Elevates Coumarin levels Transient elevation of sulfonylureas CI: Hepatic and renal dysfunction Preexisting gallbladder disease Bile Acid Binding Resins Cholestyramine and Colestipol Resins binds bile acids and bile salts in the small intestine Complex is excreted in feces and avoids enterohepatic circulation Consequently, intracellular cholesterol is used to produce new bile acids and salts, thus reducing total cholesterol concentration Therapeutic use: DOC w diet and combination with niacin for Type II Adverse Effects GI Disturbances Impaired absorption of Lipid soluble vitamins (A, D, E, K) Folic Acid Ascorbic Acid Interfere w intestinal absorption of drugs (will be less effective) Tetracycline, phenobarbital, digoxin, warfarin, prevastin, Fluvastatin, aspirin, and thiazide diuretics Resins should be taken 2 hours prior or 6 hours prior to food intake Cholesterol Absorption Inhibitors Ezetimibe Inhibits intestinal cholesterol absorption Reduces serum LDL and triglycerides Less impairment in absorption of fat soluble vitamins Glycemic Drugs Diabetes Mellitus Type 1: Genetic, younger patients Commonly undernourished at time of onset 5-10% of diagnosed diabetics Moderate genetic predisposition Beta cells are destroyed, eliminating the production of insulin Type II: due to diet, usually later in life (>35 years old) Commonly obese at time of onset 90-95% of diagnosed diabetics Very strong genetic predisposition Inability of Beta cells to produce appropriate quantities of insulin; insulin resistance; oth er defects Insulin Protein composed of 2 polypeptides linked by a disulfide bond Produced by the pancreatic Beta cells as the precursor protein known as pro-insulin When secreted it cleaves into Insulin and Protein C Rapid Action Insulin Regular Insulin Short acting crystalline zinc insulin Peak levels are acquired between 50-120 minutes after administration SC and IV (emergencies) Sources: recombinant and animal Lispro, Glulisine, and Aspart Insulins Modified insulin molecule that allows for a quicker time of absorption after SC administration Should be used 15 min prior to meal Peak levels are seen between 30-90 minutes after administration Usually used in combo w longer action insulin for appropriate control of glucose levels Intermediate Action Insulin Lente Insulin Mixture of semilente (30%) and ultralente (70%) insulin Onset and peak of action is slower than rapid action but longer than prolonged action Only use SC Isophane Insulin Suspension or neutral protamine Hagedorn (NPH) Intermediate duration of action Only use SC Prolonged Action Insulin Ultralente Insulin Suspension of pork and recombinant insulin Composed of large particles that dissolve slower Produce a slow onset of action w prolonged hypoglycemic effect Intensive Treatment Seeks glucose level normalization w more frequent insulin injections Goal is to achieve glucose levels of 175 mg/dl w total HbA1c of 7% This intensive therapy shows a 60% reduction of long term complications of diabetes if compared with those using standard therapies Standard Treatment Relies on insulin injections twice a day Maintaining glucose levels between 225-275 mg/dl w total HbA1c of 8-9% Complications of Therapy Coma Seizures Hypoglycemia (tachycardia, confusion, vertigo, diaphoresis) Lipodystrophy Hypersensitivity Diabetes Mellitus Type II T1: resistance of peripheral tissue absorption of glucose T2: B cells do not secrete insulin in the pancreas Oral Hypoglycemic Drugs Useful in the treatment of NIDDM in which glucose levels are NOT controlled soley by diet Most effective in young patients (<40) which has had NIDDM for <5 years? Patients w long standing NIDDM need a combo therapy w insulin injection and oral hypoglycemic drugs is the standard NEVER use in Type I DM Sulfonylureas Agents 2nd generation: Tolbutamide, Glyburide, Glipizide Rarely used today: Glimepiride, Acetohexamide, Tolazamide MOA: Stimulate insulin secretion from B cells Reduction of serum Glucagon levels Increase insulin binding to target receptors Metabolized by the liver Excreted by the liver and kidney CI: Hepatic or renal disease (accumulation leads to hypoglycemia), Pregnancy (cross BBB and may deplete the fetal pancreas of insulin) Drug Interactions Reduce Effectiveness (loss of glucose control): atypical antipsychotics, corticosteroids, diuretics, Niacin, Phenothiazines, Sympathomimetics Potentiate Effectiveness (hypoglycemia): Azole antifungals, beta-blockers, chloramphenicol, clarithromycin, monoamine oxidase inhibitors, probenecid, salicylates, sulfonamides Meglitinide Analogs Repaglinide and Nateglinide Stimulates insulin secretion by binding to ATP sensitive K+ channel of pancreatic cells It is used orally and taken 3 times per day in combo w sulfonylurea (synergistic effect providing better glucose control) Postprandial glucose regulator The incidence of hypoglycemia is lower than that of the sulfonylureas Inhibits CYP 3A4 isoenzyme Biguanides Metformin DOC in newly diagnosed diabetics MOA: reduction of hepatic gluconeogenesis, as well as hyperlipidemia (results in better control of cholesterol, LDL, and VLDL) with weight loss Doesn’t stimulate insulin secretion, possess a lower risk for hypoglycemia May be used in combo w sulfonylureas No drug metabolism Excreted in the urine Adverse effects: Mainly GI May interfere with Vit. B12 Potentially fatal lactic acidosis CI: avoid in hepatic and renal impairment patients Alpha-Glucosidase Inhibitors Acarbose Inhibits this enzyme in the brush border, decreasing the absorption of starch and disaccharides, and as such post-prandial rise of glucose is blunted It doesn’t increase insulin action on Peripheral tissue (no hypoglycemia) May be used in monotherapy, in those with controlled diet or in combination with other oral hypoglycemic agents and even insulin Adverse effects: GI disturbances Flatulence, Diarrhea, abdominal pain Thiazolidinediones Troglitazone, Pioglitazone, and Rosiglitazone Act by enhancing insulin actions in the liver and skeletal muscle Reduces hepatic gluconeogenesis Improves hyperglycemia, and hyperinsulinemia, and elevated HbA1c Counteracts insulin resistance Usually used in patients receiving insulin injections, and may lower their dose to achieve glucose control Oral absorption is enhanced when taken with food Extensively bound to albumin Metabolized in the liver (induces CYP-450) Excreted in feces Adverse effects: URI, HA, Anemia, Edema, Weight Gain, increase metabolism of OC and interference of drugs metabolized through CYP-450 Thyroid Drugs Hyperthyroidism (most commonly secondary to autoimmune disease or hormone producing tumor) Ionizing Radiation (ablation) Propylthiouracil Hypothyroidism (Primary (congenital), or secondary (most commonly autoimmune disease or ablation)) Hormone replacement Oral Levothyroxine Lecture 5: Antiarrhythmic Drugs Cardiac Conducting System S.A. Node (starts w B-cells that undergo polarization in the SA node) Inter-nodal pathways A.V. Node Bundle of His and branches Purkinje Fibers: go into atrium and ventricles (both should beat and contract at the same time) Pacemaker Cells Action Potentials Consist of THREE Phases (4, 0, and 3) (phases 1 and 2 are not present in pacemaker cells) Phase 4 SA node cells and AV node cells Gradient depolarization: pre-potential, moving from resting membrane potential (-60mV), to the threshold (-40mV) Slow influx of Na+ ions Membrane potential changes from -60mV to reach the threshold potential of -40mV The slope of this phase determines the heart rate SA node cells, normal depolarization rate 60-100 PM AV node cells, normal depolarization rate 40-60 SA node is the primary pacemaker since it has a higher depolarization rate Phase 0 Phase of depolarization (action potential) Starts when the membrane potential reaches the threshold of -40mV Opening of voltage-gated Ca2+ channels causing the influx of Ca2+ ions The influx of Ca2+ results in an upstroke in membrane potential from -40mV to +10mV Phase 3 Phase of repolarization Involves the closing of Ca2+ channels, blocking the inflow of Ca2+ ions Voltage-gated K+ channels open, allowing for efflux of K+ ions The rapid loss of K+ contributes to a rapid decrease in membrane potential from +10mV to -60mV Myocyte Action Potential Five Phases Phase 0 is the phase of depolarization Phase 1-3, phases during which repolarization occurs Phase 4 is the resting phase with NO spontaneous depolarization Phase 0 Rapid depolarization Voltage-gated Na+ channels open, causing a rapid influx of Na+ ions Membrane potential changes from -85mV to +50mV w steep upstroke caused by positive Na ions Phase 1 Inactivation of opened voltage-gated Na+ channels Activation of transient outward potassium current Slight drop in the membrane electrochemical potential (which results in the initiation of phase 2) The membrane potential drops down towards 0mV, but phase 2 takes over Phase 2 (plateau phase) Ca2+ influx occurs through the opening of voltage-gated L-type Ca2+ channels Calcium influx begins to balance the K+ efflux, creating a plateau (+50mV) Component of the Effective Refractory Period- influx of Ca2+ also stimulates the calcium release from the sarcoplasmic reticulum, which initiates muscle contraction During this process, no new action potentials can occur (Absolute Refectory Period) Phase 3 Repolarization L-type Ca2+ channels close, and K+ channels remain open A net outward positive current ensues (meaning that as positive potassium ions leave the cell, the membrane potential decreases) Negative change in the membrane potential allows more types of K+ channels (rapid delayed rectifier channels or slow voltage gated channels) to open and the membrane is repolarized to its resting membrane potential (Phase 4) Arrhythmia (short PR-supraventricular) (prolonged PR-atrioventricular block) An abnormality in Heart Rhythm: extrasystoles (PAC-Premature Atrial Contraction, PVC-Premature Ventricular Contraction) Ectopic pacemakers or disturbances in conduction (extra stimulation or defective conduction) Heart Rate High rate: tachycardia Low rate: bradycardia Sinus tachycardia and sinus bradycardia They are regular rhythms- this is NOT an arrythmia Very high or very low regular rhythm could predispose an arrhythmia EKG Wave Representation P-Wave: Depolarization of atria in response to SA node triggering PR Interval: delay of AV node to allow filling of ventricles QRS Complex: Depolarization of ventricles, triggers main pumping contractions ST Segment: Beginning of ventricle repolarization should be flat T-Wave: Ventricle repolarization Origin of Arrhythmia Altered Automaticity: altered pacemaker (not properly firing) by sympathetic nervous system Altered Conduction: firing normal, but signal afterwards is abormal Ectopic Atrial Conduction: a PAC (early beat), the signal originates from the atria AVRNT (Atrioventricular Node Re-entry Tachycardia) Antiarrhythmic Drugs Effects Increase or Decrease velocity of conduction Alter the excitability of cardiac cells Suppress abnormal automaticity They act on the AP of Cardiac Myocytes (primarily in ventricles) Antiarrhythmic Drugs Classification (based on the phase of the action potential) Class I: Na+ channel blockers (membrane stabilizing drugs)- Phase 0 Class II: Beta-adrenoceptor blockers- between Phase 3 and 4 Class III: drugs that prolong action potential duration- Phase 3 Class IV: calcium channel blockers- plateau in Phase 2 Class 1 Drugs Drugs that block the rapid inflow of Na+ ions Alters the slope amplitude of depolarization (minimize the steepness in phase 0) Variable effect on ERP and AP depending on the subclass IA- increase ERP and AP Duration (slows conduction) IB- decrease ERP and AP Duration IC- Normal ERP and AP Duration (slows down the activity of the action potenitals) Class 1A Class IA drugs slow Phase 0 depolarization, prolong action potentials, and slow conduction Quinidine: blocking of K+ channels, repolarization takes longer prolonged QT phase Isomer of quinine Effects on myocytes Membrane stabilizing effect Blocks potassium channels leading to prolongation of action potential duration > prolongation of atrial and ventricular refractory period Depress cardiac contractility ECG changes Prolongation of P-R and Q-T interval Widens QRS Complex Clinical uses Almost all types of arrhythmias Common uses: atrial flutter & fibrillation Can be used for ventricular tachycardia Maintaining sinus rhythm after D.C. (direct current) cardioversion (stabilize) Adverse Effects GIT: anorexia, nausea, vomiting, diarrhea Cardiac: Quinidine Syncope Episodes of fainting (due to torsades de pointes developing at therapeutic plasma levels) (due to prolongation of QT phase caused by K+ blockade) May terminate spontaneously or lead to a fatal ventricular fibrillation Anticholinergic adverse effects: can’t pee, see, spit, shit Cinchonism: visual disturbances, tinnitus, headache, and dizziness Hypotension Drug Interactions Increase concentration of digoxin Displacement from plasma proteins Inhibition of digoxin renal clearance Given PO (rarely given IV due to toxicity and hypotension due to alpha-blocking effect) Procainamide Like quinidine except Less toxic to the heart (can be given IV) More effective in ventricular than in atrial arrhythmias Less depression of contractility No anticholinergic or alpha-blocking actions Therapeutic uses Effective against most atrial and ventricular arrhythmias Second choice (after lidocaine) in ventricular arrhythmias after acute myocardial infarction Adverse effects In long term therapy it causes reversible SLE like syndrome in 5-15% of patients Hypotension Torsades de pointes: episodes of fainting Hallucination & Psychosis Class IB: first choice to stabilize the heart Class IB drugs shorten Phase 3 repolarization and decrease the duration of the action potential Lidocaine Uses DOC Treatment of ventricular arrhythmias in emergency (cardiac surgery, acute MI) Given IV bolus or slow infusion NOT effective in atrial arrhythmias or PO (not for supraventricular tachycardia) Adverse Effects: shorten QT segment, but this does not affect Hypotension Like other local anesthetics neurological adverse effects Paresthesia Tremor Dysarthria (slurred speech) Hearing disturbances Confusion Convulsions Mexiletine Effective orally Digitalis-induced arrhythmias Ventricular arrhythmias Adverse Effects Nausea, Vomiting Tremor, Drowsiness, Diplopia Arrhythmias & Hypotension Class IC: only in Phase 0, common good drugs Class IC drugs markedly slow Phase 0 depolarization Flecainide Used in supraventricular arrhythmias in patients w normal hearts Wolff-Parkinson-White Syndrome Very effective in ventricular arrhythmias, but very high risk of pro-arrhythmia (paradoxical effect leading to increased risk or exacerbation of already existing ones) Should be reserved for resistant arrhythmias Adverse Effects CNS: Dizziness, tremor, blurred vision, abnormal taste, paranesthesia Arrhythmias Heart failure due to negative inotropic effect (less contraction of the ventricle & can lead to heart failure. You get lowered ejection factor, causing water into the lungs) Propafenone Chemical structure similar to propranolol Has weak beta-blocking action Causes metallic taste and constipation Class II Drugs Beta-Adrenoceptor Blockers Actions Block B-1 receptors in the heart reducing the sympathetic effect on the heart Decrease automaticity of SA node and ectopic pacemakers Prolong refractory period (slow conduction) of the AV node, this helps prevent re-entry arrhythmias Clinical Uses Atrial arrhythmias (& supraventricular arrythmias) associated w emotion, exercise, and thyrotoxicosis (hyperthyroidism) WPW (wolf-Parkinson-white syndrome) Digitalis-induced arrhythmias Propranolol (b-1 specific) or Atenolol (non-specific) reduce the incidence of sudden arrhythmic death after MI, because of its ability to prevent ventricular arrhythmias Class III: prolonged refractory period, widens QRS complex, prolonged QT interval Class III drugs prolong Phase 3 repolarization without altering Phase 0 Prolong the action potential duration & refractory period Amiodarone Pharmacological Actions Main effect is to prolong the action potential duration and therefore prolong refractory period (useful in re-entry arrhythmias) Additional class 1a, 2 & 4 effects Vasodilation effects (due to its alpha adrenoceptor blocking effects and its calcium channel blocking effects) Uses Main use: serious resistant ventricular arrhythmias (very good) Very effective in many types of arrhythmias Maintenance of sinus rhythm after DC Cardioversion of atrial flutter and fibrillation Resistant supraventricular arrhythmias (e.g., WPW) Adverse effects Bradycardia (can cause paradoxical ventricular tachycardia) & heart block, heart failure If too prolonged QD premature ventricular contraction Pulmonary fibrosis (inflammatory response in lungs) Hyper- or Hypothyroidism Photodermatitis (in 25%) and skin deposits May cause bluish discoloration of the skin Tremor, HA, ataxia, paresthesia Constipation Corneal microdeposits (swirl): corneal epithelium Hepatocellular necrosis Peripheral neuropathy Ibutilide Pure class III Given by a rapid IV infusion Used for the acute conversion of atrial flutter or atrial fibrillation to normal sinus rhythm Causes QT interval prolongation, so it may precipitate Torsades de Pointes Class IV Calcium Channel Blockers Verapamil and Diltiazem Their main state of action is SA and AV nodes (slow conduction & prolong effective refractory period) (not as strong to prolong QT) Uses: causes vasodilation Atrial Arrhythmias Re-entry Supraventricular Arrhythmias (WPW) NOT effective in ventricular arrhythmias Miscellaneous Antiarrhythmic Drugs Adenosine: ER USED ONLY (decrease sympathetic effect: put pressure then administer) Naturally occurring nucleoside Negligible half-life (less than 10 seconds) Mechanism in Cardiac tissue Binds to Type 1 (A1) receptors which are coupled to Gi-proteins, activation of this pathway causes: Decrease in cAMP which inhibits L-type calcium channels (decreasing calcium influx) causing decrease in conduction velocity (negative dromotropic effect) mainly in AVN In cardiac pacemaker cells (SAN), inhibits pacemaker current, which decreases the slope of the phase 4 of pacemaker action potential (negative chronotropic effect) DOC for acute management for Paroxysmal Supraventricular Tachycardia Preferred over verapamil, safer and dose does not depress contractility Given 6 mg I.V. Bolus followed by 12 mg if necessary Adverse effects Flushing in about 20% of patients Shortness of breath and chest burning in 10% of patients (bronchospasm) Brief AV block (CI in heart block) Rarely cause hypotension, nausea, paresthesia, HA Digitalis Brady-Arrhythmias: slow pace, Vagus nerve (parasympathetic) Atropine (give in hemodynamic state: poor O2 in body & risk of organ failure) Can be used in sinus bradycardia after MI and in heart block Emergency heart block isoprenaline may be combined w atropine Nonpharmacologic Therapy of Arrhythmias Implantable Cardiac Defibrillator (IDC) Automatically detect and treat fatal arrhythmias such as ventricular fibrillation Lecture 6: Ocular Dyes Fluorescein Most frequently used Water soluble Diluted has maximum fluorescence at 530 nm Alkaline environment: blue-green fluorescence At physiological PH: yellow-green fluorescence Factor affecting fluorescence Concentration pH Presence of other substances Intensity and wavelength of light absorbed IV solution (fluorescite), and strips Fluress: combination and chlorobutanol have bacteriostatic/bactericidal effect; fluorocaine Clinical Application Examination of the ocular surface Corneal and conjunctival lesions (inflammation, ulcers, abrasions, edema, FB) Cobalt filter: detect causes vivid green fluorescence Yellow filter enhances fluorescent view Staining Not actual staining of the tissue Change in pH (anterior stroma) Increased dilution (post-surgery; seidel) RHP contact lens fitting Cobalt filter or Burton Lamp (UV C/L) Green pattern fluorescence of tear film assess fitting properties Proper fit- uniform Steep: central pooling Flat: peripheral pooling Staining vs Pooling: epithelial break vs indentation (dimple veil; limbal epithelial hypertrophy, a precursor of neovascularization or infiltration) Tear Film Integrity TBUT: stability Application supero-temporally Time interval from last blink to first sign of break w cobalt blue Less than 10 seconds suggests mucin deficiency, but not necessarily Validity of test sometimes is questionable Lacrimal Patency Jones test 1 (epiphora) Apply lower conjunctival sac Pump tears by force blinking 5 minutes Incline forward and blow nose; cotton tip applicator Best inspection w Burton Lamp Fluorescein present: positive test indicating patency Goldman Tonometry Delineates area of applanation (3.06) by visualization of mires Anesthetic minimizes fluoresceine; less effect w. benoxinate Optimal concentration 0.25% Little fluorescein, less applanation area, underestimation Too much fluorescein, more applanation pressure due to thick mires, overestimation Angiography Principles Primarily studies the vascularization of the ocular fundus and related lesions Optimal fluorescence by stimulation by wavelength light of 465 nm (maximal absorption) Emits green Fluorescence of 525 nm Binds to plasmatic proteins and RBC More binding less determination of vascular lesions Upon IV administration it circulates the body in 2-4 hours; the majority eliminated by the liver and kidneys in 24 hours, residual up to 1 week Materials Fundus camera w wavelength matched filters to ensure optimal visualiz