CVPR PROTOTYPE DRUGS

ADRENERGIC PHARMACOLOGY
Drug Class Drug Name Uses Toxicities/Side Effects Notes Adrenergic Recep- Epinephrine, -Anaphylactic shock rx (high doses) -Anxiety -Epi at low dose: tor Agonists Fenoldopam B2:bronchodilation, A1:vasocon-Tremor B2: bronchodilate, dilation of vessels, Endogenous Catestriction, decrease mucosa volume, -Headache decrease peripheral resistance in dicolamines BP, suppresses histamine release -Cerebral hemorrhage: increase astolic from mast cells in systolic BP BP, B1 increase HR, contractile force, -Limit absorption of local anesthetic -Cardiac arrhythmias CV A1=vasoconstriction output, systolic BP -Hemostasis (ENT surgery) -Epi at high dose: activates alpha re-Cardiac Arrest - A1: vasoconstrict, inceptors crease vascular resistance, redisB2: bronchodilate, A1: vasoconstrictribute blood, facilitate defibrillation tion, -Asthma: otc, B2 agonist preferred increase peripheral reistance and diastolic BP, B1: increase contractile force, CV output Norepinephrine -Septic Shock-related hypotension bc/ -Anxiety, Tremor, HA increases peripheral resistance via A1 -Cerebral Hemorrhage (increase activation BP), Cardiac arrhythmias, -reduced blood flow to kidneys due to vasoconstriction problem in pts. w/ renal disease -Septic shock (high doses) -High dose A1: vasoconstriction -Congestive heart failure: HR & contractility force via B1 (moderate doses) -Selectivity for alpha receptors -A1: vasoconstriction, increase peripheral resistance, BP, cardiac output unchanged, increase in reflex vagal activity decrease HR -Precursor of NE -Low dose: acts on D1 receptors coupled to Gs cAMP vasodilate renal beds, perfusion and glomerular filtration rate -Moderate dose: B1 adenoreceptors - HR and contractility

Dopamine

Adrenergic Recep- Isoprotor Agonistterenol -Adrenergic Agonists

-Asthma in the past -Anxiety -B2: bronchodilate -Stimulate heart in emergency -Tremor -B1: increase HR, Contractile force, carEx) Bradycardia or heart block w/ ef- -Headache diac output, systolic BP fects similar to Epi but more pro-Cerebral hemorrhage: increase -B2: dilate of vessels in skeletal muscle, nounced bronchodilaiton, heart in systolic BP GREATER decrease in peripheral resisstimulation, peripheral resistance -Cardiac arrhythmias tance and diastolic BP than EPI

-B1: Gs adenylate Dobutamine cyclase cAMP PKA stimulation of heart = constric- Albuterol tion -B2: Gs adenylate cyclase cAMP Ca influx smooth muscle relaxation Adrenergic Recep- Phenyletor Agonistphrine -Adrenergic Agonists

-Stimulate heart in heart failure & acute MI -Asthma via inhalation -Anxiety, tremor, headaches Lack of B1 activity cCardiac side ef- -Cardiac Arrhythmias fects. -Seizures -Treat premature labor by relaxing uterus

-Increase cardiac output like isoproterenol, little effect on HR and vascular -B2 selective agonists -At high doses selectivity lost -Used in conjunction w/ glucocorticoids, which B2 receptor transcription

-Used as a mydriatic for retinal exam- -Contraindicated in Pts w/: - A1 selective agonist ination Hypertension, prostatic enlarge-Eye & nasal decongestant ment, MAO inhibitors, cardiovasA1 constrict arterioles and venules, cular or cerebrovascular disease decrease mucous volume -A1: stimulate phos-Hemorrhoidal sx relief pholipase C SM -Used with anesthesia to control hycontraction; conpotensive states strict arteries; dilate Methoxam- -Used with anesthesia to control hy- A1 selective agonist pupil ine potensive states -A2: inhibit adenyClonidine -Hypertension - A2 receptor stimula-Stimulates A2 autoreceptors located in late cyclase w/ tion presynaptic adrenergic terminals & strong NE release = -Opioid withdrawal symptomatic NE release feedback; slows treatment: alpha2 adrenergic R-medisympathetic release ated inhibition of Locus coereleus fir& heart stim ing Miscellaneous Ampheta-Depression of appetite -Euphoria -Alters vesicular storage of monoamine Adrenergic Ago- mine -Narcolepsy -Psychosis transmitters and extravesicular levnists -ADD -Dependence els. -Arrhythmias-hypertension -NT pumped out by reverse action of transporters -Causes build-up of dopamine & NE Cocaine -Myocardial ischemia (suspect in -Blocks monoamine axonal terminal young pts. w/o cardiac risk fact) transporters inhibition of NE presy-Side effects same as NE naptic uptake Ephedrine -Present in herbal preparations but - HR and cardiac output; can be-Alpha and Beta agonist not used clinically lethal in pts w/ heart disease -Enhances norepi release -increases peripheral resistance -Causes CNS stimulation, bronchodilation Tyramine -Present in fermented foods -Can cause hypertensive crisis -Synthesized from tyrosine by L-amino in pts taking MAO inhibitors (b/c acid decarboxylase metabolized by MAO) -Similar action to NE -Assoc. w/ migraines

HEART FAILURE DRUGS

-Heart failure is the inability of the heart to eject or fill with blood at a rate commensurate with the requirements of metabolizing tissues; myocardial oxygen demand increases, leading to ischemia and oxidative stress myocardial remodeling (hypertrophy, apoptosis, fibrosis, dilation). -Heart failure causes decreased cardiac output, increased sympathetic drive, and increased Epi (alpha 1 vasoconstriction, beta 1 increased contractile force, CO, & BP) & NE (alpha 1 vasoconstriction & increased peripheral resistance & BP). This causes increased overall contractility force, HR, & arterial tone increased myocardial O2 demand, ischemia, and oxidative stress myocardial maladaptive structural changes/remodeling hypertrophy, apoptosis, fibrosis, dilation. -Decreased perfusion to the kidneys causes activation of the renin-angiotensin-aldosterone pathway, resulting in vasoconstriction and sodium & water retention. -Sx: Left heart failure dyspnea, orthopnea, decreased exercise tolerance, weakness; Right heart failure edema, hepatomegaly, exercise intolerance, systemic venous distent. -Non-pharmacologic tx: smoking cessation, regular exercise, healthy diet (limit Na+ intake), weight loss, no alcohol or drug use

Drug Class Drug Name ACE Inhibitors Captopril

Mechanism of Action -Blockade of ACE, decreasing angiotensin II and aldosterone levels this causes vasodilation, less sodium & water retention, and decreases K+ loss -Also inhibits breakdown of bradykinin, which promotes vasodilation by increasing NO and prostaglandin levels

Toxicities/Side Effects -Side effects: dry cough & angioedema (puffy face, secondary to increase in bradykinin), and hyperkalemia -Contraindications: renal failure, hyperkalemia, pregnancy -Drug interactions: NSAIDS will prevent the increase in prostaglandin levels induced by ACE inhibition

Notes -ACE is an endothelial luminal ectoenzyme common in pulmonary capillaries that cleaves angiotensin I into angiotensin II -ACE inhibitors prevent the build-up of angiotensin II & aldosterone -Benefits: vasodilation, control of remodeling

Angiotensin Losartan II Receptor Antagonists

Diuretics

-Same as ACE Inhibitors except do not -Side effects: hyperkalemia ONLY affect bradykinin -Contraindications: renal failure, hyperkalemia, pregnancy -Drug interactions: NSAIDS will prevent the increase in prostaglandin levels induced by ACE inhibition Thiazide - Hy- -Inhibits Na+ reabsorption in the DCT drocholorothiazide Loop -Inhibits Na+ reabsorption in the asFurosemide cending loop of Henle

Potassiumsparing Spironolactone

Beta block- Propranolol, ers Metoprolol Positive Ionotropic Agents Digoxin

-Antagonizes the aldosterone receptors -Toxicity: hyperkalemia in pts w/ renal dis- -Weak diuretic that controls the (decreases function of Na+/K+ pump) ease or those taking ACE inhibitors, anactions of aldosterone (antagoon the collecting tubule, blocking their giotensin II receptor antagonists, or beta- nist) K is not pumped in stimulatory effects on the transcription blockers; build-up to K+ in serum ardecreased fluid reabsorption of proteins that enhance activity of lu- rhythmia minal channels and ATPase in the col- -Side effects: gynecomastia, impotence, lecting tubule menstrual abnormalities -Counteract harmful effects of sympathetic overactivation decrease renin production & remodeling -Inhibits the Na+/K+ ATPase, indirectly -Contraindications: hypokalemia assoc w/ -Only used when pt. not reinhibiting Na+/Ca2+ exchange inthe use of thiazide & loop diuretics sponding to other meds creased intracellular Ca2+ improved -Inhibition of ATPase in GI tract = diarrhea, -Useful when the problem is decontraction vomiting, visual disurbances, disorientacreased contractility -Indirect electrical effects via parasym- tion in the elderly pathetic action causes membrane hy- -At toxic concentrations hypokalemia perpolarization & decreases automatic- sympathetic outflow is increased causes ity (useful in tx of arrhythmias) arrhythmias -Anti-digoxin antibodies can be used to treat toxicity

ANTIARRHYTHMIC DRUGS

Drug Class Class I Na+ channel blockers

Drug Name Mechanism of Action Group IA Quinidine, Procainamide

Uses

Toxicities/Side Effects

Notes

-Major action: block Na+ chan- -Quinidine helps to -Adverse effects: proarrhythmia -AP effects: slow upstroke of nels (phase 0) maintain sinus (torsade de point caused by delay AP, prolong duration of AP, in-Secondary action: inhibit derhythm in atrial fibril- in phase 3 of AP - EAD) more likely crease refractory period layed rectifier K+ channels inlation or flutter in hypokalemic pts -ECG effects: prolong QT involved in repolarization/K+ efflux -Procainamide is 2nd -diarrhea, nausea, vomiting, -cin- terval (phase 3) choice for treatment chonism (headache, dizziness, tin-Block activated Na+ channels of ventricular arnitus) and remain bound to inactivated rhythmias -vagolytic effects: facilitate AV channel for an intermediate perinodal conduction od -Procainamide produces a lupus-like -Intermediate kinetics syndrome (rash on face, arthralgia, arthritis) in 30% of pts -Drug interactions: increased risk of TDP w/ quinine, quinolones, macrolides

Group IB -Major action: block open Na+ -Ventricular arrhyth- -Adverse effects: restlessness & -AP effects: no effect on duraLidocaine, channels from inside & briefly re- mias: predominantly tremor tion, small reduction in ampliMexiletine main bound to inactivated chan- acts on Purkinje & -High doses: convulsins, seizures, tude nel ventricular muscle respiratory depression, arteriolar -Lidocaine: IV administration -Predominantly acts on Purkinje &cells dilation, cardiovascular collapse -Mexiletine: oral administraventricular muscle cells -Nystagmus is an early sign of lido- tion resistant to 1st pass -Dissociates w/ rapid kinetics caine toxicity metabolism in liver -Effect is dependent on pH only uncharged base can cross the membrane Group IC -Major action: block open Na+ -Supraventricular ar- -Adverse effects: heart failure exac- -AP effects: minimal effect on Flecainide, channels from inside & remain rhythmias in pts with erbation, increased mortality post AP duration, small reduction Propafenon bound to inactivated channel for otherwise normal MI in AP amplitude e, Morilong amt of time hearts -ECG effects: little effect on cizine -Also blocks delayed rectifier K+ QT; prolong QRS channel -Dissociates w/ slow kinetics Class II Propra-Major action: block cardiac ef-Termination of re-en- -Adverse effects: bronchospasm -AP effects: decrease the block- nolol, Estrant AV node ar(esp w/ propranolol); bradycardia; slope of SA node AP & defects of -receptor activation, ers molol, heart block; aggravation of heart crease AP rate which normally stimulates chan- rhythmias Metoprolol nels involved in phases 4 & 0 -Control of ventricu- failure in uncompensated pts; de- -ECG effects: increase PR (AV node depressant effect) decrease SA node firing freq. lar response in atrial crease hypoglycemia recovery; fibrillation complicate peripheral vascular dis- -Propranolol reduces HR (B1) increase AV node conduction time prolong AV refractoriness -Control of arrhyth- ease; increase triglycerides & lower & prolongs bronchospasm HDL cholesterol; angina & rebound (B2) & decrease AV node automaticity mias triggered by stress hypertension in abruptly with-Metoprolol is cardioselective -Reduction of lifedrawn; depression; sedation; sleep & reduces HR (B1) threatening arrhyth- disturbances; sexual dysfunction mias post-MI -Contraindications: sympathomimetics Class III Amiodarone-Major action: K+ channel in-IV acute therapy of -Adverse effects: pulmonary fibro- -AP effects: prolongs AP, efK+ chanhibiton ventricular tachycar- sis; bradycardia; hypotension (betal fective refractory per. nel in-Secondary actions: Na+ channel dia or fibrillation re- blockade); torsade de pointes; hy- -ECG effects: PR; prolong hibitors sistant to other drugs perthyroidism; corneal microdeQRS; prolong QT (K+ block) blockade, blockade, Ca2+ -Maintenance of si- posits; gray-blue skin discoloration channel blockade -Similar mechanism as quinidine nus rhythm in pts w/ w/ sun exposure atrial fibrillation -Arrhythmia prophylaxis post-MI

Class IV Verapamil, -Major action: block L-type VGCC, -Supraventricular ar- -Adverse effects: exacerbate heart -AP effects: decrease the L-type Diltiazem which mediate phase 0 of the rhythmias failure; bradycardia; constipation slope of phase 0 for SA & AV VGCC nodal AP decrease SA node fir- -Useful in pts w/ co- -Drug interactions: combined IV ad- node APs; decrease firing blockers ing frequency increase AV morbid conditions: min w/ a beta blocker can result in rate; affect phase 2 of AP in node conduction time & prolong hypertension, angi- asystole; heart block can occur in ventricular muscle AV node refractoriness na, & Raynauds syn- pts w/ digitalis toxicity -ECG effects: increase PR -SA & AV node conduction dedrome pression Misc. Adenosine -Produces similar actions to acti- -Used IV to terminate -ECG effects: increase PR vation of M2 receptors by vagal re-entrant supravenACh release; binds to A1 recep- tr. arrhythmias tors inhibits cAMP inhibition -Short-acting of VGCC -Larger doses reqd -Effects: HR, impulse spread in pts that have takthroughout atria; AV node auto- en caffeine (adenomaticity & AP rate; AV node sine antagonist) conduction time & refractory period Digoxin -Indirect inhibitory actions on the Na+/Ca2+ exchanger causes activation of K+ channels -Inhibits Na+/K+ ATPase -Parasympathomimetic actions: increase resting membrane potential, decreases automaticity Magnesium -Unknown mechanism of action -Re-entrant arrhyth- -At toxic concentrations, sympa-AP effects: shortens AP duramias involving the AVthetic outflow is increased caus- tion node es arrhythmias -Control of ventricular response in atrial fibrillation -Useful in the treatment of torsade de pointes & arrhythmias induced by digitalis toxicity

ASTHMA & COPD DRUGS

-Asthma: airflow limitation largely reversible; airway hyperresponsiveness significant; characterized by the presence of eosinophils, CD4+ Th2 lymphocytes, activation of mast cells, IL-4 & IL-5, fragile epithelium, thickened basement membrane, mucus metaplasia, glandular enlargement; clinical course early onset, varying/intermittent sx, often FH, presence of allergy, rhinitis -Treatment: hyperresponsiveness of trachea and bronchi to stimuli & contraction of airway smooth muscle treated w/ 2 agonist, theophylline, antimuscarinics, leukotriene modifiers; mucosal thickening from edema often leading to a mucus plug in airway lumen & cellular infiltration treated w/ corticosteroids, leukotriene modulators, mast cell stabilizer, anti-IgE, theophylline -Short-term relief: bronchodilating agents to increase airway caliber by relaxing smooth muscles -adrenergic agonists, theophylline, antimuscarinics -Long-term control: anti-inflammatory agents to edema, mucus, & infiltration inhaled corticosteroids, antileukotrienes, mast cell stabilizer, anti-IgE, 2 agonists -COPD: airflow limitation largely irreversible; airway hyperresponsiveness variable; characterized by the presence of neutrophils, macrophages, CD8+ T cells, IL-8, TNF-, squamous metaplasia of epithelium, parenchymal destruction, mucus metaplasia, glandular enlargement; clinical course midlife onset, usually due to smoking, slowly progressive sx, persistent airflow obstruction after admin. of albuterol Drug Class Selective 2 agonist Drug Name Albuterol, Terbutaline, Metaproterenol Mechanism of Action Pharmacokinetics / Notes -Cause bronchodilation & in- -Acute bronchospasm-Side effects: skeletal muscle -Short-acting: act in 30 min, hibit the release of bron(asthma) airflow tremor (B2), tachycardia (B1), last 3-4 hrs choconstricting substances (most effective drug) tachyphylaxis (drug becomes -Inhaled drug should be from mast cells & increase -Terbutaline can be less effective d/t receptor down- poorly absorbed through GI mucociliary transport given SC for emer- regulation), nausea, vomiting, & rapidly inactivated via 1st -Acts by binding to beta2 gencies headache, hypokalemia pass elim. activating Gs increasing -Also used to prevent -Selective for 2, so less cardiac -Beta 2 selectivity is lost if adenylate cyclase increas- exercise-induced 1 side effects given a high dose or if ading cAMP smooth muscle asthma -Contraindications: ministered another route relaxation bronchodilation -Modest prolongation of QT in- besides inhalation terval -Cause bronchodilation & inhibit the release of bronchoconstricting substances from mast cells & increase mucociliary transport -Acts by binding to beta2 activating Gs increasing adenylate cyclase increasing cAMP smooth muscle relaxation bronchodilation -Moderate persistent -Side effects: skeletal muscle -Long-acting: lasts 12 hrs or severe persistent tremor, tachycardia (B1), tachy- -Used w/ corticosteroids asthma increase phylaxis, nausea, vomiting, -Inhaled drug should be airflow & decrease headache, hypokalemia poorly absorbed through GI exacerbations -Selective for 2, so less cardiac & rapidly inactivated via 1st -Especially used for 1 side effects pass elim. nocturnal sx & exer- -Contraindications: cise-induced asthma -Modest prolongation of QT in-Not for acute rescue terval or sole therapy Uses Toxicities/Side Effects

Selective 2 agonist

Salmeterol

1,2 & 1,2 agonist

Epinephrine

Muscarinic An- Ipratropium tagonists bromide, Tiotropium

-Bronchodilator via binding to -Not commonly used -Nonselective agent, so has mabeta 2 receptors today for asthma b/c jor B1 side effects: tachycardia, nonselective arrhythmias, worsening of angina -Acts at M1 & M3 receptors -Inhalation treatment -Well-tolerated as inhaled -Is a relatively weak broninhibits bronchoconstriction for COPD d/t smok- preparation (low lipid solubility, chodilator, has no anti-indue to release of ACh from va- ing, less effective for poorly absorbed into CNS) flammatory activity, & does gus nerve efferents opens asthma -Systemically can cause similar not decrease bronchial hyairway -Used in asthma pts effects as atropine: dry mouth, perresponsivness -Inhibits tracheobronchial se- intolerant to beta ag- palpitations, blurred vision, concretions onists or as an adstipation junct therapy -Higher doses: hallucinations, tachycardia, urinary retention -Contraindication: glaucoma -Side effects: nausea, vomiting, -Related to uric acid headache, insomnia, nervous- -Direct positive chronotropness, diarrhea, tachycardia, ar- ic & inotropic effects rhythmias -Low concentrations: inhibi-Causes mild cortical arousal by tion of presynaptic adenoincreasing catecholamine levels sine thereby increasing cat-Stimulates secretion of gastric echolamine release acid & digestive enzymes -High concentrations: di-High doses can cause hyrectly increase Ca2+ influx pokalemia, hyperglycemia by inhibiting PDE skeletal muscle tremor, and seizures -Hepatic metabolism drug interxs -Leukotrienes are potent mediators released from mast cells, eosinophils, & basophils that contract airway smooth muscle, vascular perm., mucus secretions & attract inflammatory cells in the airways of asthma pts.

Methylxanthine

Theophylline -Relaxes constricted bronchi & -3rd or 4th line treatrelieves airflow obstruction ment for acute & se-Inhibits the breakdown of vere asthma cAMP (inhibits phosphodiesterase) and activity of adenosine receptors on bronchial smooth muscle cells -Activates histone deacetylases in the nucleus -could transcription of several proinflammatory genes & potentiate the effect of corticosteroids

Leukotriene Zafirlukast Antagonists & Synthesis Inhibitors

-Acts as a competitive antago- -Maintenance treat- -Well-tolerated nist at the CysLT1 receptor, ment for mild to -Adverse effects: GI disturpreventing leukotrienes from moderate asthma bances, mild headache binding inhibits bronan alternative to low- -Inhibits CYP3A4 & CYP2C9 so choconstriction dose inhaled cortiaffects co-administered drugs -Inhibits CYP2C9, increasing costeroid therapy that are metabolized by these warfarin life enzymes -Taking it with food bioavailability

-Inhibits 5-lipoxygenase, -For mild to moderthereby reducing the levels of ate asthma an alall leukotrienes inhibits ternative to low-dose bronchoconstriction inhaled corticos-Also inhibits CYP3A4 & can teroid therapy influence the metabolism of terfenadine, warfarin, & theophylline Glucocorticoid Hydrocorti-Have no action on airway -Most effective agent -Side effects linked to route & -Oral, parenteral, & inhaled sone, Methyl- smooth muscle but reduce in treating inflamma- dosage: glucose intolerance, administrations prednisolone, bronchial reactivity & increase tory response in immunosuppression, bone dem- -Liver metabolism Prednisone, airway caliber asthma, so can use ineralization, weight gain, -Actions that help to reduce Beclometha- -Sensitize beta receptors for severe, acute, & cataracts, increased bp, deinflammation: inhibition of sone, Flutca- -Repress cytokine gene tran- chronic asthma creased growth rate mediator synthesis, stabisone scription: Inhibit PLA2 produc- -Can prevent in-Suppression of adreno-pituitary lization of cell membranes, tion of arachidonate by increase in reactivity axis (after 2 wks) w/ parenteral & the redistribution & inhicreasing transcription of associated w/ late or oral prep bition of leukocytes lipocortin-1, thereby decreas- asthmatic response -Throat thrush, hoarseness w/ -Glucocorticoids also reing LTX, PG, & platelet activat- to allergens inhaled prep store the beta adrenergic ing factor production receptor response bronchodilation Cromolyn Cromolyn sodium, Nedocromil -Alters Cl- channel function -Used prophylactical- -Few side effects b/c poorly ab- -IgE antibody-antigen interinhibits Ca2+ influx inhibits ly to inhibit sorbed (administered via inhala-action of the mast cell mast cell function prevents antigen/allergy & ex- tion) leads to an influx of Ca2+ release of histamine & LTX ercise-induced asth- -Side effects: throat irritation, into the cells releases -May inhibit the function of ma cough, bronchospasm, mouth histamine, leukotrienes other inflammatory cells -Not useful during an dryness, chest tightness, -Does not directly relax acute episode wheezing bronchial smooth muscle -Recombinant monocolonal -Administered over -Side effects: anaphylaxis & maantibody that binds to IgE 10 wks for those with lignancies cant bind to mast cell & ba- poorly controlled or sophil receptors no allergic severe persistent reaction asthma to reduce -Reduces serum levels of free magnitude of early & IgE late bronchospasm -Reduces tissue eosinophils responses and bronchial IgE mast cells & does not provoke degranulation

Zileuton

Anti-IgE Anti- Omalizumab body

DIURETICS

-Excess ECW causes edema, high blood pressure, increased work by heart -ECW is most efficiently decreased by Na+ loss (water follows Na+). Pure water loss is diuresis, pure sodium loss is natriuresis. Most diuretics cause both. -Ceiling Dose: Increasing dose adds no beneficial effect; Increasing dose could cause detrimental side effects; Site and mechanism of action determine ceiling efficacy loop diuretic have a higher ceiling dose & can cause a greater vol loss (higher efficacy) compared to thiazide diuretics -Combining diuretics: Potassium sparing diuretics combined with diuretics acting at site 1, 2 or 3 prevent or correct hypokalemia; Combining loop diuretic with thiazide diuretic can greatly increase efficacy with low doses of both drugs. Combining drugs acting at the same site is not synergistic. Changes in Urinary Electroytes Group NaCl NaHCO3 CA Inhibitor + +++ Loop diuretics ++++ 0 Thiazides ++ + Loop + thiazides +++++ + K+ sparing + (+) K+ + + + ++ Body pH + + + -

Drug Class Drug Name Mechanism of Action Carbonic AcetazolaAnhydrase mide Inhibitor

Pharmacokinetics / Notes -Inhibits carbonic anhydrase to in-Open angle glauco- -Quinidine excretion is decreased -Orally absorbed crease luminal [HCO3-] in the proximal ma (inhibits formation (anion transporter) and its action is and secreted into tubule of enhanced (hypokalemia). tubule lumen. -Decreases Na+ reabsorption and H+ aqueous humor) = -Hyperchloremic metabolic acidosis -High levels of CA secretion by luminal Na+/H+ exchang- most common indica- (HCO3- loss) require high doses er water is held in tubule tion -Alkaline urine increases excretion to significantly -Decreases passive Cl- reabsorption. -Alkalinization of the and precipitation of Ca2+ and decrease Na+ ex-Increased delivery of Na+ to the distal urine (i.e. increases phosphate to enhance renal stone cretion. nephron causes K+ loss. excretion of weak formation. -Ineffective when acids such as urate -Hypokalemia total body bicarand -Hypersensitivity reactions, espe- bonate is low. cystine) to treat gout cially in cases of hepatic cirrhosis. -Only effective for -Correct metabolic ala few days bekalosis (i.e. diuretic-incause bicarbonate duced alkalosis in is heart fail.) by excreting depleted HCO3(acidosis). -Mountain sickness -Na+ reabsorption (low pH increases venat later segments tilation and CA contriblimits the efficacy utes to CSF formation) of site 1 diuretics -Moderate efficacy (35% Na+ lost) and rapid refractoriness limit usefulness as diuretic.

Uses

Toxicities/Side Effects

Osmotic Di- Mannitol uretics

-Reduces tubular water reabsorption in -Effective even w/ re- Acute expansion of extracellular -Mannitol not aball duced GFR to prevent fluid volume caused by the osmotic sorbed from GI segments of the tubule. renal failure and con- effect of mannitol leads to side ef- tract so must be -Reduces net tubular Na+ reabsorpsequential tubular fects: administered IV. tion: Retained water reduces tubule damage. -Headache -Glycerin and Na+ concentration Na+ diffuses into -Reduces intracranial -Nausea isosorbide are proximal tubules (down its concentra- pressure in certain -Vomiting orally active tion gradient) neurological -Chest pain agents. -Drug held in tubule to exert osmotic situations. Hyponatremia -Ideal osmotic press. to hold water in the tubule & in- -Reduces intraocular Exacerbate congestive heart fail- diur.: crease water excretion shifts water pressure in glaucoma ure. -Distribute only in from ICW to ECW (emergency vascular fluid com-Water retention decreases renin secre- situations, before or afpartment tion and reduces blood viscosity. ter surgical treatment). -Pharmacologically -Decreased ion transport in loop of inert Henle reduces medullary gradient. -Not metabolized -Increase medullary RBF to wash NaCl -Readily filtered at and urea out of medulla and promote glomerulus diuresis. -Not reabsorbed -Markedly increases urine flow and exfrom tubules cretion of Na+, Ca2+, and Cl- w/ little effect on HCO3- & K+

Loop Diuretic

Furosemide Torasemide Ethacrynic acid

-High ceiling diuretics (up to 25% of -Congestive heart -K+ wasting drug leads to negafiltered Na+ load) failure: venodilation tive side effects -Secreted via proximal tubule anion ex- decrease preload, -Hypovolemia (hypotension) changer. alleviate pulmonary -Hyponatremia, hypocalcemia, -Inhibit Na/K/2Cl symport in thick edema, decrease ede- hypochloremic metabolic alkalosis, ascending limb. ma hypokalemia (cardiac arrhythmias) -Na+ gradient facilitates K+ and Cl- re- -Renal disease (in-Decreased GFR if systemic presabsorption via basolateral symporter. cluding acute renal sure decreases too much -K+ re-enters tubule through apical failure & nephrotic syn--Ototoxicity channel while Cl- exits through basolat- drome): reduce ede- -Hyperuricemia (gout): due to reeral channel. ma, maintain RBF to tention of uric acid -Na+ reabsorption in thick ascending preserve GFR -Infrequent cases of insulin resislimb = 25% filtered load. -Cirrhosis: reduce tance b/c hypokalemia decreases -in Na delivery to the distal tubule edema insulin sensitivity, which increases K+ and H+ excretion (hypokalemic -Other edematous hyperglycemia metabolic alkalosis). states: stimulate wa- -Digitalis: Hypokalemia can in-Increase RBF by stimulating PG syn- ter loss crease digitalis-induced arrhyththesis (generalized vasodilation) mias. -NaCl delivery to macula densa cells -Glucocorticoids: Inherent minerblocks tubuloglomerular feedback alocorticoid activity can induce fludecreased regulation of GFR id retention to antagonize diuretic -Vol loss stimulates renin release response, produce additive K+ loss and SNSA. and additive glucose intolerance. -NSAIDs: Inhibition of renal and vascular prostaglandin production blunts diuretic and vasodilating effects. -Aminoglycoside antibiotics: Augment ototoxicity. -Pharmacokinetic drug interactions: Compete for clearance w/ other weak acidic drugs. Compete w/ other plasma protein bound drugs & can cause acute spike in plasma conc. when other drugs are released

-Readily absorbed orally. -Fast onset (1 60 min) with short half lives (0.3 6 hrs), so safe & efficacious

Thiazides

Hydro-Only 5% of Na load enters distal choloro-thi- tubule. azide -Inhibit NaCl symporter on luminal membr. -Cl- absorbed against its concentration gradient (exits passively through a basolateral channel). -Na+ delivery to distal tubule K+ and H+ loss K+ wasting -Ca2+ excretion by unknown mechanism

-Hyponatremia -NOT effective with -Volume depletion and hypotension, impaired GFR can decrease RBF and GFR. -Does NOT affect - Hypokalemia, risk for torsades tubulo-glomerular de pointes (prolongation of the QT feedback (doesnt interval) w/quinidine (compete for increase renin seanion transporter) cretion). -Hypomagnesemia, Hypercalcemia -Hypokalemia decreased insulin sensitivity, LDL cholesterol (contraindicated in diabetes) -Most serious and potentially fatal -Inhibition of H+ side effect is hyperkalemia K+ secretion may albuild-up in plasma kalinize the urine. -Metabolic acidosis most likely in pts w/ impaired renal function or excessive potassium intake d/t K/H exchange -Potassium supplements are generally not given with these drugs -ACE inhibitors and beta-blockers may exacerbate hyperkalemia. -Decrease Ang II decrease aldosterone exacerbate hyperkalemia

Na+ Chan- Amiloride -Inhibit luminal sodium channel of prinnel InTriamterene cipal cells (ENaC). hibitors -Affect primarily late distal tubules & early collecting ducts - Na/K exchange -Potassium-sparing diuretics. -Decrease Na+ reabsorption and K+ and H+ secretion in proximal cells. -Oppose effects of aldosterone. -Inhibit K+ secretion secondary to decreased Na+ entry. -Reduce H+ secretion, perhaps by inhibiting Na+-H+ transporter.

Mineralo- Spironolac- -Binds to & blocks mineralocorticoid R -Can prevent or recorticoid tone in late distal tubule and early collecting verse hypomagneAntagonists Eplerenone duct. semia and hypocal-Inhibits mineralocorticoid-dependent cemia induced by thiretention of NaCl and water and excre- azides and loop tion of K+ and H+. diuretics. -Blocks aldosterone decreased Na/K ATPase activity prevents reabsorption at late tubule -Exerts a Mg2+- and Ca2+-sparing effect by ill-defined mechanisms. -Opposes mineralocorticoid actions: Activate luminal Na channels (ENaC) Synthesize new channels (ENaC) Activate Na/K-ATPase Increase ATP synthesis

-Increases Na+ and Cl- excretion -Synthetic steroid and decreases loss of K+ , Mg2+ -Require endogeand H+ Hyperkalemia and meta- nous bolic acidosis. aldosterone to be -Anti-androgenic effects (spirono- effective lactone) can lead to menstrual irregularities and gynecomastia and impotence in males. -Eplerenone avoids anti-androgenic effects.

Vasopressin Conivaptan Antagonists: Aquaretics

-Correct hyponatremia by blocking AVP -Used for treatment of binding to the V2 receptor in luminal hyponatremia (excess membrane of collecting free water). duct cells restores plasma [Na+], decreases water permeability, & increases free water clearance. - Inhibits ADH-dependent retention of water in collecting duct.

-Increased plasma osmolality -Dry mouth -Thirst -Polyuria

ANTIHYPERTENSIVE DRUGS

-HTN health effects: left ventricular hypertrophy; heart failure; arrhythmias & ischemia; aortic dissection; retinopathy; dementia & stroke (hemorrhagic & ischemic); nephrosclerosis; renal insufficency -Hypertensive urgency: BP must be reduced within a few hrs to avoid organ damage; classified as asymptomatic severe HTN (>220/>120 mmHg) that is persistent or severe HTN assoc w/ optic disk edema, progressive target organ complications, or within the perioperative period -Hypertensive emergency: BP must be reduced within an hr to avoid death; classified as severe HTN (>220/>120) assoc w/ encephalopathy, neuropathy, intracranial hemorrhage, aortic dissection, preeclampsia, pulmonary edema, unstable angina, & MI; parenteral therapy red target = gradual decrease in BP (by 25% 1-2 hr, then 160/100 mmHg within 2-6 hr) -Non-pharmacological therapy: weight reduction (BMI 18-25 lowers systolic BP 5-20 mmHg / 10 kg loss); DASH eating plan (eat fruits & vegetables lowers systolic BP 8-14 mmHg); decrease Na+ intake (lowers systolic BP 2-8 mmHg); physical activity (lowers systolic BP 4-9 mmHg); decrease alcohol intake (limit to 1-2 drinks/day in men & 1 drink for women lowers systolic BP 2-4 mmHg); quit smoking (lowers systolic BP 2-4 mmHg after 1 wk) -HTN + Diabetes: ACE Inhibitor + Angiotensin II receptor antagonist slow progression of diabetic nephropathy -HTN + Stable angina pectoris: blocker or long-acting Ca2+ channel blocker -HTN + Acute coronary syndromes (unstable angina or MI): blocker and ACE Inhibitor -HTN + Heart failure: blocker, ACE Inhibitor, & diuretic -HTN + Chronic kidney disease: aggressive BP management; ACE Inhibitor, ARB, loop diuretic -HTN + Hyperthyroidism: use blocker to prevent the increase in systolic BP & HR Classification of Hypertension (>18 years of age) Category Systolic Diastolic Normal<120 <80 Prehypertension 120-139 80-89 Stage 1 140-159 90-99 Stage 2 >160 >100

Drug Class Drug Name

Mechanism of Action

Uses

Toxicities/Side Effects

Diuretic

Thiazide diuretics - Hydrochlorothiazide

-Primary mechanism: Blocks the -Low doses are commonly Na+/Cl- co-transporter on the luminal used to treat uncomplicated side of the DCT (where 10% of Na+ is HTN as monotherapy or in reabsorbed) increased excretion of combination w/ other agents NaCl & H2O & decreased intravascu- -Requires 2-4 weeks to act, lar vol & cardiac output so do not use in HTN emer-Secondary mechanism: during gencies chronic therapy, thiazides decrease interstitial fluid & vascular stiffness vasodilation decrease in peripheral resistance

-Hypokalemia due to increased luminal Na+ being exchanged for K+ in the collecting tubule, causing excess K+ loss; complicates arrhythmias & inhibits insulin release, causing hyperglycemia; use with K+-sparing diuretics or ACE inhibitors to minimize hypokalemia -Impotence, muscle cramps, weakness -Hypercalcemia due to a decrease in intracellular Na+ increases Na+/Ca2+ exchanger activity increased reabsorption of Ca2+; could be useful in pts w/ osteoporosis -Increase in LDL & VLDL -Increase in uric acid levels contraindicated w/ gout -Drug interactions: contraindicated in pts allergic to sulfonamides -Not effective in pts w/ decreased renal function

Loop diuretic -Blocks the Na+/K+/2Cl- symporter -Hypertensive emergencies -Same as for thiazides on thick ascending loop of Henle assoc w/ acute pulmonary -Also cause calciuria & ototoxicity Furosemide increased excretion of NaCl & H2O edema, acute renal failure, & -Drug interactions: do not use with other decreased intravascular vol & cardiac heart failure drugs that produce ototoxicity (aminoglycoside output antibiotics, for ex) -Decreased import of K+ causes hypomagneisa & hypocalcemia by decreasing transepithelial potential difference that drives paracellular entrance of Mg2+ & Ca2+ Potassium-Amiloride & Triamterene Block Na+ -Ameliorate hypokalemia pro- -Hyperkalemia in pts w/ renal disease or those sparing dichannels, preventing exchange w/ duced by thiazide or loop di- taking ACE inhibitors, angiotensin II receptor anuretic K+ in collecting tubule uretics tagonists, or beta blockers (B1 receptors work in Amiloride, Tri- -Spironolactone blocks the aldosthe kidney) amterene, terone receptor, decreasing ex-Spironolactone: gynecomastia, impotence, Spironolacchange in collecting tubule & DCT menstrual problems tone -Adrener- Clonidine, -Acts on brainstem pressor centers, -Substitute drug in cases of -Sedation, depression gic Agonist Methyldopa sensitizing them to inhibition by poor resistance, side effects, -Xerostomy (dry mouth) (2 selective), baroreceptor reflexes reduced NE or contraindications to 1st -Sexual dysfunction Methyloxam- release presynaptically decreased line treatments (thiazide di- -Rebound HTN upon abrupt withdrawal; Hyperine, Phenyle- sympathetic outflow decreased uretics, beta blockers, ACE tensive crisis must be treated w/ alpha & beta phrine (1 se- cardiac output & peripheral resisinhib) blocker lective) tance -Usually used w/ a diuretic -Drug interactions: tricyclic antidepressants -Autoreceptors limit synaptic trans- -Hypertensive urgencies inhibit hypotensive effect & clonidine reduces mission by inhibiting transmitter re- -Methyldopa is used to treat antidepressant action; rebound HTN upon Clonolease presynpatically HTN in pregnancy dine withdrawal

-Adrener- Prazosin gic Antagonist

-Decrease peripheral resistance (af- -Uncomplicated HTN as a 2nd -Postural hypotension sudden syncope terload) & venous return to the heart or substitute drug -Fluid retention (avoid though use in combina(preload) -3rd drug in unresponsive pts tion w/ a diuretic) -Reduction in preload reduces cardiac -Beneficial in pts w/ HTN & -Monotherapy can increase CHF output = little reflex tachycardia dislipidemia, premature ejac- -Drug interactions: aggravation of 1st dose ulation, or prostatic hyperpla-syncope when used w/ ACE inhibitor or beta sia (blocks alpha 1 trigone blocker & sphincter smooth muscle relaxation facilitates micturition)

-Adrener- Propranolol -Decrease HR & contractility re-Uncomplicated HTN as a -Bronchospasm w/ non-selective agents gic Antago- (non-selective), duction in cardiac output monotherapy or in combina- -Bradycardia - aggravation of heart failure in unnist Metoprolol -Decrease rennin production de- tion w/ other agents compensated pts (cardioseleccrease Ang II decrease peripheral -HTN complicated by MI, A-V -Decrease in hypoglycemia recovery intive), Esmolol resistance & aldosterone secretion node arrhythmias, migraines, creased risk for diabetes type II & masking of (short-acting, less water & Na+ retention hyperthyroidism, and/or com-hypoglycemic signs cardioselective -Propranolol (noselective, 1 & 2, pensated heart failure -Aggravation of peripheral vascular -disease for emergenfull agonist) reduces HR & produces (non-selective agents) cies) ABEAM = bronchospasm -Increase in triglycerides & decrease HDL Acebutolol, -Metoprolol (cardioselective, 1 at -Angina & rebound HTN upon withdrawal Betaxolol, Es- low doses) reduces HR & produces -Depression, sedation, sleep disturbances, sexumolol, less bronchospasm al dysfunction Atenolol, -Pindolol (nonselective, partial ago-Drug interactions: bradycardia & heart block Metoprolol nist) & Acebutolol (cardioselective) when used w/ voltage-gated Ca2+ channel have partial agonist actions (intrinsic blockers; hypertensive crisis when used w/ Epi sympathomimetic activity) & produce (unopposed stimulation of 1); decreased hepatless bronchospasm & lipid alterations ic clearance when used w/ cimetidine & fluoxetine & Labetalol, Adrenergic Carvedilol Receptor Blockers -Labetalol indicated for HTN emergencies (IV) except acute heart failure -Carvedilol not commonly used for HTN; used for heart failure

ACE Inhibitors

Captopril, Lisinopril

-Block ACE decrease Ang II & al-1st line therapy for young -Increased lung bradykinin levels can cause dry dosterone levels vasodilation, less Caucasian pts cough & angioedema, leukopenia, loss of taste Na+ & H2O retention, decreased K+ -1st line therapy for pts w/ -Hyperkalemia loss HTN & diabetes, renal failure, -Use w/ caution in pts w/ renal failure use low-Inhibits breakdown of bradykinin myocardial ischemia, or CHF; er dose & monitor K+ & Renal stenosis marked increases nitric oxide & prostaglandin can be used as monotherapy hypotension, reversible renal dysfunction due to levels vasodilation or in combination w/ diuretic decrease in glomerular filtration in stenotic kid-IV therapy for hypertensive ney emergencies -Contraindicated in pregnancy fetal death, kid-Heart failure: controls re- ney failure, malformations modeling by causing vasodi- -Drug interactions: do not use with K+ sparing lation; decreases mortality diuretic d/t hyperkalemia; NSAIDs will prevent the increase in prostaglandin levels induced by ACE Inhib

Angiotensin Losartan II Receptor Anatagonists (ARBs)

-Antagonizes A-II receptor de-Same as ACE Inhibitor crease Ang II & aldosterone levels vasodilation, less Na+ & H2O retention, decreased K+ loss -Do not affect bradykinin

-Same as ACE Inhibitor except does NOT cause dry cough or angioedema

Ca2+ Chan- Verapamil, nel Antago- Diltiazem, nists Nifedipine / Dihydropyridines

-Inhibit VSM contraction

-2nd or 3rd line therapy -Exacerbate CHF, fluid retention -Useful in emergencies -Excessive depression of SA & AV nodes (in pts -1st line therapy in elderly & w/ ventricular tachycardia = ventricular fibrillaAfrican American pts tion & hemodynamic collapse) -Pts w/ comorbid conditions -Decreased heart contractility bradycardia such as angina, atrial fibrilla- -Constipation d/t intestinal smooth muscle relaxtion, & Raynauds syndrome ation -Not effective as monothera- -Short-acting dihydropyridines can increase risk py b/c of physiologic comof MI by decreasing BP too quickly pensatory response: sys-Drug interactions: combined IV admin of vertemic vascular resistance & apamil & a beta blocker can result in asystole; arterial pressure activates heart block can occur when combined with digiRAS & sympathetic outflow talis toxicity aldosterone, renal Na+ excretion plasma vol, peripheral resistance, & CO compensatory in BP

Direct-act- Arterial Hy- -Decrease peripheral resistance (af- -3rd drug in unresponsive pts -Lupus-like syndrome ing Vadralazine, Mi- terload) by increasing K+ channel -HTN in pts w/ eclampsia -Tachycardia sodilators noxidil opening, causing hyperpolarization or-Usually used in combination -Aggravates angina VSM w/ a beta blocker (to prevent -Fluid retention reflex tachycardia) & a diuretic (to prevent fluid retention) -Heart failure (BiDil) Arterial & ve- -Predominantly relax veins (& arter- -Hypertensive emergencies -Orthostatic hypotension nous Niies), decrease preload & afterload, & assoc w/ acute pulmonary -Reflex tachycardia trates (Nitro- dilate coronary arteries edema, myocardial ischemia, -Headache, increased intracranial pressure glycerine, Dini- -Act as nitric oxide donors stimu- & aortic dissection -Tolerance trate isosorlate guanylyl cyclase increase -Treats angina, ischemic HD, -Fluid retention (d/t increase in aldosterone) bide), Sodium cGMP activate PKG decrease cy- & heart failure (in combina- -Methemoglobulinemai (Hb w/ ferric iron) at toxnitroprusside toplasmic Ca2+ levels & activate tion w/ hydralazine) ic doses (useful in treatment of cyanide poisonmyosin light chain phosphatase -Treatment of cyanide poison- ing) smooth muscle relaxation ing produces methe-Drug interactions: hypotension when used e/ moglobinemia leads to sidenafil transfer of cyanide from mitochondria to circulation

HEMOSTATIC & THROMBOSIS DRUGS

Drug Class Anticoagu-lant

Drug Name Mechanism of Action Heparin

Uses

Toxicities/Side Effects -Bleeding, thrombocytopenia, osteoporosis -Heparin-Induced Thrombocytopenia (HIT): type 1 caused by heparin interacting w/ platelets leading to low platelet aggregation (non-immune); type 2 causes pt to develop thrombi & is d/t IgG antibody against PF4-heparin complex (immune form) -Reversal in the OR w/ protamine sulfate

-Catalyzes activation of antithrom- -Immediately supbin III Binds to endothelium & press blood coagulaantithrombin III inhibits activat- tion in thromboemed coagulation factors thrombin bolic disorders (PE, (IIa), plasmin, Xa, IXa, Xia, XIIa, stroke, angina, MI, and kallikrein DVT) -Can be used during pregnancy (doesnt cross placenta

Pharmacokinetics / Notes -IV or SubQ not absorbed from GI tract -Negatively charged & binds to plasma proteins -Must perform blood coagulation tests aPTT

Low Molecu- -Same as heparin but with a -Anticoagulation lar Weight greater capacity to potentiate facHeparin tor Xa inhibition by antithrombin Enoxaprin, than thrombin (chains too short to Dalteparin, bridge antithrombin to thrombin) -Inhibits Xa>IIa Warfarin -Blocks the gamma carboxylation (Coumadin), of glutamine residues in all the viDicumarol tamin K dependent clotting factors: prothrombin, factors VII, IX, X, protein C -Anticoagulation effect seen in 24 hrs, so initiate w/ heparin or direct thrombin inhibitors

-Risk of bleeding -Longer life -Lower risk of osteoporosis -Better bioavailability -Less effect on platelet function less -SubQ admin inhibited by platelet factor IV (de-No monitoring necescreased likelihood of an immune resary sponse) -Not as easily reversible -Chronic anticoagula- -Significant drug interactions -1/2 life ranges from tion (not for rapid an- -Risk of bleeding: increases w/ age, 25-60 hrs (long!) ticoagulation may renal failure, recent trauma or surgery, -Duration of action for take a few days for prior hx of bleed, HTN, drug interaca single dose is 2-5 clinical effect) tions days -For thromboembolic -99% plasma protein bound drug in- -Reversal w/ Vit K disease & ischemic teractions -Cytochrome P-450 mestroke in pts w/ atrial -Efficacy decreased by increased levels tabolism fibrillation of Vit K in diet, liver disease, broad -Follow PT/INR levels spectrum antibiotics Increases PT -Warfarin-induced skin necrosis -Fetal toxic (contraindicated in pregnancy) -Use w/ caution in HIT & DVT pts induce limb gangrene (insufficient protein C) -Must monitor INR levels

Indirect Fondaparin- -Synthetic pentasaccharide w/ se- -Anticoagulation Thrombin ux lective antifactor Xa activity Inhibitor -Binds irreversibly w/ high affinity to AT, thus inhibiting factor Xa but not thrombin (pentasaccharide is too short to bridge antithrombin to thrombin) -Reduces thrombin generation but no direct actions on thrombin

-Does not induce allergic response (synthetic agent) -Elevated drug levels can occur in pts w/ renal insufficiency bleeding -Cross-reactivity with antibodies causing HIT does not occur -No antidote (reversal)

Danaparoid -AT-dependent anticoagulant w/ -Can be used to treat -Not reversible by protamine sulfate predominant antifactor Xa activity pts w/ HIT Direct Hirudin, Thrombin Lepirudin Inhibitors -Inactivates bound fibrin with action independent of antithrombin III & little effect on platelets -Not inactivated by antiheparin proteins -Use as an alternative to heparin for anticoagulating pts w/ HIT

-Plasma life of 24 hrs -Renal clearance -Produced in the salivary gland of leech

Argatroban -Synthetic L-arginine derivative -Prophylaxis of HIT that acts as a competitive inhibitor -Drug of choice for of thrombin (thrombolytic) pts w/ renal impairment Ximelaga-Dipeptide that mimics the thromtran bin binding site of fibrinopeptide A (thrombolytic)

-Cleared by the liver -IV admin t1/2 = 45 min -Can increase alanine aminotransferase levels (reversible) -Lipophillic prodrug of melagatrain -Oral admin -Kidney excretion

Protein C Drotrecogni -Recombinant form of human acti- -Prevents death d/t -Bleeding n alpha vated Protein C that inhibits coag- sepsit if given within ulation by proteolytic inactivation 48 hrs of onset of orof factors Va & VIIIa gan failure -Anti-inflammatory effects Thrombo- Alteplase (t- -Derived from recombinant human -Uses: lysis of acute -Contraindicated in pts w/ severe HT, lytics PA), Uroki- tissue plasminogen activator & pulmonary thromhx of bleeding, recent surgery nase works as a plasminogen activator boembolism or acute -Converts plasminogen to plasmin coronary arterial by directly hydrolyzing the argithromboembolism nine-valine bound in plasminogen; assoc w/ evolving MI plasmin degrades fibrin & fibrino- -Clot-specific action gen as well as the procoagulant (does not cause a factors V & VIII lytic state) -Activity dependent on presence of fibrin

-Parenteral

Streptoki-Nonspecific plasminogen activanase, APSAC tor (circulating & bound) indirect action by forming a noncovalent compound w/ plasminogen -Induces procoagulant response via increased release of thrombin

-Uses: acute MI, pul- -High potential for antigenicity monary embolism, -Contraindicated in pts w/ severe HT, DVT, occluded arteri- hx of bleeding, recent surgery ovenous cannulae, & acute arterial thrombosis & embolism

-Rarely used

Antifibri- Aminocaproi -Inhibits fibrinolysis -Can treat thromno-lytic c Acid bolytic toxicity Antiplate- Aspirin -Acetylates irreversibly inhibit cy- -Antipyretic let / Anclooxygenase to prevent conver- -Analgesic tithromsion of arachidonic acid to throm- -Anti-inflammatory botic boxane A2 (TXA2) prevents -Antiplatelet drug platelet aggregation increase bleeding time Ticolpidine, -Irreversibly block ADP receptors -Uses: completed Clopidogrel prevents glycoprotein IIb/IIIa ex- strokes, unstable pression inhibits ADP-induced angina, transient isbinding of fibrinogen to platelet chemic attacks, membrane inhibits platelet ad- acute coronary synhesion drome, coronary -Affects blood viscosity & reduces stenting fibrinogen concentration Cilostazol, -Inhibit phosphodiesterase (PDE) -Cilostazol is used to Dipyritype III prevents the breakdown treat intermittent damole of cAMP increases cAMP levels claudication in platelets increases vasodila- -Decrease triglyction & inhibits platelet aggrega- erides & increase tion HDL cholesterol Abiciximab -Noncompetitive inhibitor / monoclonal antibody to GPIIb/IIIa receptor on activated platelets prevents binding of vWF blocks platelet plug formation (fibrin binding) & aggregation

-Gastric ulceration -Bleeding -Hyperventilation -Reyes syndrome -Tinnitis (CN VIII)

-No effect on PT, PTT

-GI disturbance, Hemorrhage, Leukope- -Req blood testing for nia, neutropenia, TTP, BM toxicity 1st 3 mos

-Used with aspirin

-Thrombotic arterial -Bleeding disease -Thrombocytopenia -Unresponsive unstable angina -Reduce risk of MI

-Very effective: 2 hrs after admin, 80% of GP IIb/IIIa receptors are blocked & platelet aggregation is almost nonexistant