CVPR PROTOTYPE DRUGS

ADRENERGIC PHARMACOLOGYDrug Class Drug Name Uses Toxicities/Side Effects Notes

Adrenergic Re-ceptor Agonists – Endogenous Cate-colamines

Epinephrine, Fenoldopam

-Anaphylactic shock rx (high doses) B2:bronchodilation, A1:vasocon-striction, decrease mucosa volume, ↑BP, suppresses histamine release from mast cells-Limit absorption of local anesthetic A1=vasoconstriction-Hemostasis (ENT surgery)-Cardiac Arrest - A1: vasoconstrict, increase vascular resistance, redis-tribute blood, facilitate defibrillation-Asthma: otc, B2 agonist preferred

-Anxiety-Tremor-Headache-Cerebral hemorrhage: increase in systolic BP-Cardiac arrhythmias

-Epi at low dose: B2: bronchodilate, dilation of vessels, decrease peripheral resistance in di-astolic BP, B1 increase HR, contractile force, CV output, systolic BP-Epi at high dose: activates alpha re-ceptors B2: bronchodilate, A1: vasoconstric-tion, increase peripheral reistance and di-astolic BP, B1: increase contractile force, CV output

Norepine-phrine

-Septic Shock-related hypotension bc/ increases peripheral resistance via A1 activation

-Anxiety, Tremor, HA-Cerebral Hemorrhage (in-crease BP), Cardiac arrhyth-mias, -reduced blood flow to kidneys due to vasoconstriction – prob-lem in pts. w/ renal disease

-Selectivity for alpha receptors-A1: vasoconstriction, increase periph-eral resistance, BP, cardiac output un-changed, increase in reflex vagal ac-tivity decrease HR

Dopamine -Septic shock (high doses) -High dose A1: vasoconstriction-Congestive heart failure: ↑ HR & contractility force via B1 (moderate doses)

-Precursor of NE-Low dose: acts on D1 receptors cou-pled to Gs ↑ cAMP vasodilate renal beds, ↑ perfusion and glomerular fil-tration rate-Moderate dose: B1 adenoreceptors - ↑ HR and contractility

Adrenergic Re-ceptor Agonist-β-Adrenergic Ago-nists

Isopro-terenol

-Asthma in the past-Stimulate heart in emergency Ex) Bradycardia or heart block w/ effects similar to Epi but more pro-nounced – bronchodilaiton, heart stimulation, ↓ peripheral resistance

-Anxiety-Tremor-Headache-Cerebral hemorrhage: increase in systolic BP-Cardiac arrhythmias

-B2: bronchodilate-B1: increase HR, Contractile force, cardiac output, systolic BP-B2: dilate of vessels in skeletal mus-cle, GREATER decrease in peripheral resistance and diastolic BP than EPI

-B1: Gs adenylate cyclase ↑ cAMP ↑ PKA stimulation of heart = constric-tion-B2: Gs adenylate cyclase ↑ cAMP ↑ Ca influx smooth muscle re-laxation

Dobutamine -Stimulate heart in heart failure & acute MI

-Increase cardiac output like isopro-terenol, little effect on HR and vascu-lar

Albuterol -Asthma via inhalation Lack of B1 activity ↓cCardiac side effects.-Treat premature labor by relaxing uterus

-Anxiety, tremor, headaches-Cardiac Arrhythmias-Seizures

-B2 selective agonists-At high doses selectivity lost-Used in conjunction w/ glucocorti-coids, which ↑ B2 receptor transcrip-tion

Adrenergic Re-ceptor Agonist-α-Adrenergic Ago-nists

-A1: stimulate phos-pholipase C SM contraction; con-strict arteries; dilate pupil-A2: inhibit adeny-late cyclase w/ strong NE release = feedback; slows sympathetic release & ↓ heart stim

Phenyle-phrine

-Used as a mydriatic for retinal ex-amination-Eye & nasal decongestant A1 constrict arterioles and venules, decrease mucous volume-Hemorrhoidal sx relief-Used with anesthesia to control hy-potensive states

-Contraindicated in Pts w/:Hypertension, prostatic en-largement, MAO inhibitors, car-diovascular or cerebrovascular disease

- A1 selective agonist

Methoxam-ine

-Used with anesthesia to control hy-potensive states

- A1 selective agonist

Clonidine -Hypertension - A2 receptor stimula-tion-Opioid withdrawal symptomatic treatment: alpha2 adrenergic R-me-diated inhibition of Locus coereleus firing

-Stimulates A2 autoreceptors located in presynaptic adrenergic terminals & ↓ NE release

Miscellaneous Adrenergic Ago-nists

Ampheta-mine

-Depression of appetite-Narcolepsy-ADD

-Euphoria-Psychosis-Dependence-Arrhythmias-hypertension

-Alters vesicular storage of monoamine transmitters and ↑ ex-travesicular levels. -NT pumped out by reverse action of transporters-Causes build-up of dopamine & NE

Cocaine -Myocardial ischemia (suspect in young pts. w/o cardiac risk fact)-Side effects same as NE

-Blocks monoamine axonal terminal transporters inhibition of NE presy-naptic uptake

Ephedrine -Present in herbal preparations but not used clinically

-↑ HR and cardiac output; can be lethal in pts w/ heart disease-increases peripheral resistance

-Alpha and Beta agonist-Enhances norepi release-Causes CNS stimulation, bronchodila-tion

Tyramine -Present in fermented foods -Can cause hypertensive crisis in pts taking MAO inhibitors (b/c metabolized by MAO)-Assoc. w/ migraines

-Synthesized from tyrosine by L-amino acid decarboxylase-Similar action to NE

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; my-ocardial oxygen demand increases, leading to ischemia and oxidative stress myocardial remodeling (hypertrophy, apoptosis, fibrosis, dila-tion).-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 contractil-ity 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 in-tolerance, 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 Mechanism of Action Toxicities/Side Effects Notes

ACE In-hibitors

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

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

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

Angiotensin II Receptor Antagonists

Losartan -Same as ACE Inhibitors except do not affect bradykinin

-Side effects: hyperkalemia ONLY-Contraindications: renal failure, hyper-kalemia, pregnancy-Drug interactions: NSAIDS will prevent the increase in prostaglandin levels in-duced by ACE inhibition

Diuretics Thiazide - Hy-drocholoroth-iazide

-Inhibits Na+ reabsorption in the DCT

Loop - Furosemide

-Inhibits Na+ reabsorption in the as-cending loop of Henle

Potassium-sparing – Spironolac-tone

-Antagonizes the aldosterone recep-tors (decreases function of Na+/K+ pump) on the collecting tubule, block-ing their stimulatory effects on the transcription of proteins that enhance activity of luminal channels and ATP-ase in the collecting tubule

-Toxicity: hyperkalemia in pts w/ renal dis-ease or those taking ACE inhibitors, an-giotensin II receptor antagonists, or beta-blockers; build-up to K+ in serum ar-rhythmia-Side effects: gynecomastia, impotence, menstrual abnormalities

-Weak diuretic that controls the actions of aldosterone (antago-nist) K is not pumped in de-creased fluid reabsorption

Beta block-ers

Propranolol, Metoprolol

-Counteract harmful effects of sympa-thetic overactivation – decrease renin production & remodeling

Positive Ionotropic Agents

Digoxin -Inhibits the Na+/K+ ATPase, indirectly inhibiting Na+/Ca2+ exchange in-creased intracellular Ca2+ improved contraction-Indirect electrical effects via parasym-pathetic action – causes membrane hyperpolarization & decreases auto-maticity (useful in tx of arrhythmias)

-Contraindications: hypokalemia assoc w/ the use of thiazide & loop diuretics-Inhibition of ATPase in GI tract = diar-rhea, vomiting, visual disurbances, disori-entation in the elderly-At toxic concentrations hypokalemia sympathetic outflow is increased causes arrhythmias-Anti-digoxin antibodies can be used to treat toxicity

-Only used when pt. not re-sponding to other meds-Useful when the problem is de-creased contractility

ANTIARRHYTHMIC DRUGS

Drug Class

Drug Name Mechanism of Action Uses Toxicities/Side Effects Notes

Class I –Na+ channel blockers

Group IA – Quinidine, Pro-cainamide

-Major action: block Na+ chan-nels (phase 0)-Secondary action: inhibit de-layed rectifier K+ channels in-volved in repolarization/K+ ef-flux (phase 3)-Block activated Na+ channels and remain bound to inactivated channel for an intermediate pe-riod-Intermediate kinetics

-Quinidine helps to maintain sinus rhythm in atrial fib-rillation or flutter-Procainamide is 2nd choice for treatment of ventricular ar-rhythmias

-Adverse effects: proarrhythmia (torsade de point – caused by de-lay in phase 3 of AP - EAD) more likely in hypokalemic pts-diarrhea, nausea, vomiting, -cin-chonism (headache, dizziness, tin-nitus)-vagolytic effects: facilitate AV nodal conduction-Procainamide produces a lupus-like syndrome (rash on face, arthralgia, arthritis) in 30% of pts-Drug interactions: increased risk of TDP w/ quinine, quinolones, macrolides

-AP effects: slow upstroke of AP, prolong duration of AP, increase refractory period-ECG effects: prolong QT in-terval

Group IB – Lidocaine, Mexiletine

-Major action: block open Na+ channels from inside & briefly remain bound to inactivated channel-Predominantly acts on Purkinje & ventricular muscle cells-Dissociates w/ rapid kinetics-Effect is dependent on pH – only uncharged base can cross the membrane

-Ventricular arrhyth-mias: predominantly acts on Purkinje & ventricular muscle cells

-Adverse effects: restlessness & tremor-High doses: convulsins, seizures, respiratory depression, arteriolar dilation, cardiovascular collapse-Nystagmus is an early sign of lido-caine toxicity

-AP effects: no effect on du-ration, small reduction in amplitude-Lidocaine: IV administration-Mexiletine: oral administra-tion – resistant to 1st pass metabolism in liver

Group IC – Flecainide, Propafenone, Mori-cizine

-Major action: block open Na+ channels from inside & remain bound to inactivated channel for long amt of time-Also blocks delayed rectifier K+ channel-Dissociates w/ slow kinetics

-Supraventricular ar-rhythmias in pts with otherwise normal hearts

-Adverse effects: heart failure ex-acerbation, increased mortality post MI

-AP effects: minimal effect on AP duration, small reduc-tion in AP amplitude-ECG effects: little effect on QT; prolong QRS

Class II – β block-ers

Propra-nolol, Es-molol, Metoprolol

-Major action: block cardiac ef-fects of β-receptor activation, which normally stimulates chan-nels involved in phases 4 & 0 decrease SA node firing freq. increase AV node conduction time prolong AV refractoriness & decrease AV node automatic-ity

-Termination of re-entrant AV node ar-rhythmias-Control of ventricu-lar response in atrial fibrillation-Control of arrhyth-mias triggered by stress-Reduction of life-threatening arrhyth-mias post-MI

-Adverse effects: bronchospasm (esp w/ propranolol); bradycardia; heart block; aggravation of heart failure in uncompensated pts; de-crease hypoglycemia recovery; complicate peripheral vascular dis-ease; increase triglycerides & lower HDL cholesterol; angina & rebound hypertension in abruptly withdrawn; depression; sedation; sleep disturbances; sexual dys-function-Contraindications: sympath-omimetics

-AP effects: decrease the slope of SA node AP & de-crease AP rate-ECG effects: increase PR (AV node depressant effect)-Propranolol reduces HR (B1) & prolongs bronchospasm (B2)-Metoprolol is cardioselective & reduces HR (B1)

Class III – K+ chan-nel in-hibitors

Amio-darone

-Major action: K+ channel in-hibiton-Secondary actions: Na+ chan-nel blockade, β blockade, Ca2+ channel blockade-Similar mechanism as quinidine

-IV acute therapy of ventricular tachycar-dia or fibrillation re-sistant to other drugs-Maintenance of si-nus rhythm in pts w/ atrial fibrillation-Arrhythmia prophy-laxis post-MI

-Adverse effects: pulmonary fibro-sis; bradycardia; hypotension (be-tal blockade); torsade de pointes; hyperthyroidism; corneal microde-posits; gray-blue skin discoloration w/ sun exposure

-AP effects: prolongs AP, ↑ effective refractory per.-ECG effects: ↑ PR; prolong QRS; prolong QT (K+ block)

Class IV – L-type VGCC blockers

Verapamil, Diltiazem

-Major action: block L-type VGCC, which mediate phase 0 of the nodal AP decrease SA node firing frequency increase AV node conduction time & prolong AV node refractoriness-SA & AV node conduction de-pression

-Supraventricular ar-rhythmias-Useful in pts w/ co-morbid conditions: hypertension, angina, & Raynaud’s syndrome

-Adverse effects: exacerbate heart failure; bradycardia; constipation-Drug interactions: combined IV admin w/ a beta blocker can result in asystole; heart block can occur in pts w/ digitalis toxicity

-AP effects: decrease the slope of phase 0 for SA & AV node APs; decrease firing rate; affect phase 2 of AP in ventricular muscle-ECG effects: increase PR

Misc. Adenosine -Produces similar actions to acti-vation of M2 receptors by vagal ACh release; binds to A1 recep-tors inhibits cAMP inhibition of VGCC-Effects: ↓ HR, ↓impulse spread throughout atria; ↓ AV node au-tomaticity & AP rate; ↑ AV node conduction time & refractory pe-riod

-Used IV to termi-nate re-entrant supraventr. arrhyth-mias-Short-acting-Larger doses req’d in pts that have taken caffeine (adenosine antago-nist)

-ECG effects: increase PR

Digoxin -Indirect inhibitory actions on the Na+/Ca2+ exchanger causes activation of K+ channels-Inhibits Na+/K+ ATPase-Parasympathomimetic actions: increase resting membrane po-tential, decreases automaticity

-Re-entrant arrhyth-mias involving the AV node -Control of ventricu-lar response in atrial fibrillation

-At toxic concentrations, sympa-thetic outflow is increased causes arrhythmias

-AP effects: shortens AP du-ration

Magnesium -Unknown mechanism of action -Useful in the treat-ment of torsade de pointes & arrhyth-mias induced by dig-italis 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 en-largement; 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/ β2 agonist, theo-phylline, antimuscarinics, leukotriene modifiers; mucosal thickening from edema often leading to a mucus plug in airway lumen & cellular infil-tration treated w/ corticosteroids, leukotriene modulators, mast cell stabilizer, anti-IgE, theophylline-Short-term relief: bronchodilating agents to increase airway caliber by relaxing smooth muscles β-adrenergic agonists, theophylline, an-timuscarinics-Long-term control: anti-inflammatory agents to ↓ edema, mucus, & infiltration inhaled corticosteroids, antileukotrienes, mast cell stabi-lizer, anti-IgE, β2 agonists -COPD: airflow limitation largely irreversible; airway hyperresponsiveness variable; characterized by the presence of neutrophils, macrophages, CD8+ T cells, IL-8, TNF-α, squamous metaplasia of epithelium, parenchymal destruction, mucus metaplasia, glandular enlarge-ment; clinical course – midlife onset, usually due to smoking, slowly progressive sx, persistent airflow obstruction after admin. of albuterol

Drug Class Drug Name Mechanism of Action Uses Toxicities/Side Effects Pharmacokinetics / Notes

Selective β2 agonist

Albuterol, Terbutaline, Metapro-terenol

-Cause bronchodilation & in-hibit the release of bron-choconstricting substances from mast cells & increase mucociliary transport-Acts by binding to beta2 activating Gs increasing adenylate cyclase increas-ing cAMP smooth muscle relaxation bronchodilation

-Acute bron-chospasm (asthma) – ↑ airflow (most ef-fective drug)-Terbutaline can be given SC for emer-gencies-Also used to pre-vent exercise-in-duced asthma

-Side effects: skeletal muscle tremor (B2), tachycardia (B1), tachyphylaxis (drug becomes less effective d/t receptor down-regulation), nausea, vomiting, headache, hy-pokalemia-Selective for β2, so less car-diac β1 side effects-Contraindications: -Modest prolongation of QT in-terval

-Short-acting: act in 30 min, last 3-4 hrs-Inhaled drug should be poorly absorbed through GI & rapidly inactivated via 1st

pass elim.-Beta 2 selectivity is lost if given a high dose or if ad-ministered another route besides inhalation

Selective β2 agonist

Salmeterol -Cause bronchodilation & in-hibit the release of bron-choconstricting substances from mast cells & increase mucociliary transport-Acts by binding to beta2 activating Gs increasing adenylate cyclase increas-ing cAMP smooth muscle relaxation bronchodilation

-Moderate persistent or severe persistent asthma – increase airflow & decrease exacerbations-Especially used for nocturnal sx & exer-cise-induced asthma-Not for acute rescue or sole therapy

-Side effects: skeletal muscle tremor, tachycardia (B1), tachyphylaxis, nausea, vomit-ing, headache, hypokalemia-Selective for β2, so less car-diac β1 side effects-Contraindications: -Modest prolongation of QT in-terval

-Long-acting: lasts 12 hrs-Used w/ corticosteroids-Inhaled drug should be poorly absorbed through GI & rapidly inactivated via 1st

pass elim.

α1,2 & β1,2 agonist

Epinephrine -Bronchodilator via binding to beta 2 receptors

-Not commonly used today for asthma b/c nonselective

-Nonselective agent, so has major B1 side effects: tachy-cardia, arrhythmias, worsening of angina

Muscarinic An-tagonists

Ipratropium bromide, Tiotropium

-Acts at M1 & M3 receptors inhibits bronchoconstriction due to release of ACh from vagus nerve efferents opens airway-Inhibits tracheobronchial se-cretions

-Inhalation treat-ment for COPD d/t smoking, less effec-tive for asthma-Used in asthma pts intolerant to beta agonists or as an ad-junct therapy

-Well-tolerated as inhaled preparation (low lipid solubility, poorly absorbed into CNS)-Systemically can cause similar effects as atropine: dry mouth, palpitations, blurred vision, constipation-Higher doses: hallucinations, tachycardia, urinary retention-Contraindication: glaucoma

-Is a relatively weak bron-chodilator, has no anti-in-flammatory activity, & does not decrease bronchial hyperresponsiv-ness

Methylxan-thine

Theophylline -Relaxes constricted bronchi & relieves airflow obstruction-Inhibits the breakdown of cAMP (inhibits phosphodi-esterase) and activity of adenosine receptors on bronchial smooth muscle cells-Activates histone deacety-lases in the nucleus -could ↓ transcription of several proin-flammatory genes & potenti-ate the effect of corticos-teroids

-3rd or 4th line treat-ment for acute & se-vere asthma

-Side effects: nausea, vomiting, headache, insomnia, nervous-ness, diarrhea, tachycardia, ar-rhythmias-Causes mild cortical arousal by increasing catecholamine levels-Stimulates secretion of gastric acid & digestive enzymes-High doses can cause hy-pokalemia, hyperglycemia skeletal muscle tremor, and seizures-Hepatic metabolism drug in-terxs

-Related to uric acid-Direct positive chronotropic & inotropic effects -Low concentrations: inhi-bition of presynaptic adenosine thereby increas-ing catecholamine release-High concentrations: di-rectly increase Ca2+ influx by inhibiting PDE

Leukotriene Antagonists & Synthesis In-hibitors

Zafirlukast -Acts as a competitive antag-onist at the CysLT1 receptor, preventing leukotrienes from binding inhibits bron-choconstriction-Inhibits CYP2C9, increasing warfarin ½ life

-Maintenance treat-ment for mild to moderate asthma – an alternative to low-dose inhaled corticosteroid ther-apy

-Well-tolerated -Adverse effects: GI distur-bances, mild headache-Inhibits CYP3A4 & CYP2C9 so affects co-administered drugs that are metabolized by these enzymes-Taking it with food ↓ bioavail-ability

-Leukotrienes are potent mediators released from mast cells, eosinophils, & basophils that contract air-way smooth muscle, ↑ vascular perm., ↑ mucus secretions & attract inflam-matory cells in the airways of asthma pts.

Zileuton -Inhibits 5-lipoxygenase, thereby reducing the levels of all leukotrienes inhibits bronchoconstriction-Also inhibits CYP3A4 & can influence the metabolism of terfenadine, warfarin, & theo-phylline

-For mild to moder-ate asthma – an al-ternative to low-dose inhaled corticos-teroid therapy

Glucocorticoid Hydrocorti-sone, Methyl-prednisolone, Prednisone, Beclometha-sone, Flutca-sone

-Have no action on airway smooth muscle but reduce bronchial reactivity & in-crease airway caliber-Sensitize beta receptors-Repress cytokine gene tran-scription: Inhibit PLA2 pro-duction of arachidonate by increasing transcription of lipocortin-1, thereby decreas-ing LTX, PG, & platelet acti-vating factor production

-Most effective agent in treating inflamma-tory response in asthma, so can use for severe, acute, & chronic asthma-Can prevent in-crease in reactivity associated w/ late asthmatic response to allergens

-Side effects linked to route & dosage: glucose intolerance, immunosuppression, bone demineralization, weight gain, cataracts, increased bp, de-creased growth rate-Suppression of adreno-pitu-itary axis (after 2 wks) w/ par-enteral or oral prep-Throat thrush, hoarseness w/ inhaled prep

-Oral, parenteral, & inhaled administrations-Liver metabolism-Actions that help to re-duce inflammation: inhibi-tion of mediator synthesis, stabilization of cell mem-branes, & the redistribu-tion & inhibition of leuko-cytes-Glucocorticoids also re-store the beta adrenergic receptor response bron-chodilation

Cromolyn Cromolyn sodium, Ne-docromil

-Alters Cl- channel function inhibits Ca2+ influx inhibits mast cell function prevents release of histamine & LTX-May inhibit the function of other inflammatory cells-Does not directly relax bronchial smooth muscle

-Used prophylacti-cally to inhibit anti-gen/allergy & exer-cise-induced asthma-Not useful during an acute episode

-Few side effects b/c poorly ab-sorbed (administered via in-halation)-Side effects: throat irritation, cough, bronchospasm, mouth dryness, chest tightness, wheezing

-IgE antibody-antigen inter-action of the mast cell leads to an influx of Ca2+ into the cells releases histamine, leukotrienes

Anti-IgE Anti-body

Omalizumab -Recombinant monocolonal antibody that binds to IgE can’t bind to mast cell & ba-sophil receptors no allergic reaction-Reduces serum levels of free IgE-Reduces tissue eosinophils and bronchial IgE mast cells & does not provoke degranu-lation

-Administered over 10 wks for those with poorly con-trolled or severe per-sistent asthma to re-duce magnitude of early & late bron-chospasm responses

-Side effects: anaphylaxis & malignancies

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 di-uretics-Combining diuretics: Potassium sparing diuretics combined with diuretics acting at site 1, 2 or 3 prevent or correct hypokalemia; Combin-ing loop diuretic with thiazidediuretic can greatly increase efficacy with low doses of both drugs. Combining drugs acting at the same site is not synergistic.

Changes in Urinary ElectroytesGroup NaCl NaHCO3 K+ Body pHCA Inhibitor + +++ + -Loop diuretics ++++ 0 + +Thiazides ++ + + +Loop + thiazides +++++ + ++ +K+ sparing + (+) - -

Drug Class Drug Name Mechanism of Action Uses Toxicities/Side Effects Pharmacokinet-ics / Notes

Carbonic Anhydrase Inhibitor

Acetazola-mide

-Inhibits carbonic anhydrase to in-crease luminal [HCO3-] in the proxi-mal tubule-Decreases Na+ reabsorption and H+ secretion by luminal Na+/H+ ex-changer water is held in tubule-Decreases passive Cl- reabsorption.-Increased delivery of Na+ to the dis-tal nephron causes K+ loss.

-Open angle glau-coma (inhibits forma-tion ofaqueous humor) = most common indica-tion-Alkalinization of the urine (i.e. increasesexcretion of weak acids such as urate andcystine) to treat gout-Correct metabolic al-kalosis (i.e. diuretic-in-duced alkalosis in heart fail.) by excret-ing HCO3--Mountain sickness (low pH increases ven-tilation and CA con-tributes to CSF forma-tion) -Moderate efficacy (3-5% Na+ lost) and rapidrefractoriness limit usefulness as diuretic.

-Quinidine excretion is decreased (anion transporter) and its action is enhanced (hypokalemia).-Hyperchloremic metabolic acido-sis (HCO3- loss)-Alkaline urine increases excretion and precipitation of Ca2+ and phosphate to enhance renal stone formation.-Hypokalemia-Hypersensitivity reactions, espe-cially in cases of hepatic cirrhosis.

-Orally absorbed and secreted into tubule lumen.-High levels of CA require high doses to significantlydecrease Na+ ex-cretion.-Ineffective when total body bicar-bonate is low.-Only effective for a few days be-cause bicarbonate isdepleted (acido-sis).-Na+ reabsorption at later segments limits the efficacy of site 1 diuretics

Osmotic Di-uretics

Mannitol -Reduces tubular water reabsorption in allsegments of the tubule.-Reduces net tubular Na+ reabsorp-tion: Retained water reduces tubule Na+ concentration Na+ diffuses into proximal tubules (down its concentra-tion gradient)-Drug held in tubule to exert osmotic press. to hold water in the tubule & in-crease water excretion shifts water from ICW to ECW-Water retention decreases renin se-cretion and reduces blood viscosity.-Decreased ion transport in loop of Henle reduces medullary gradient.-Increase medullary RBF to wash NaCl and urea out of medulla and promote diuresis.-Markedly increases urine flow and ex-cretion of Na+, Ca2+, and Cl- w/ little effect on HCO3- & K+

-Effective even w/ re-duced GFR to prevent renal failure and con-sequential tubular damage.-Reduces intracranial pressure in certain neurologicalsituations.-Reduces intraocular pressure in glaucoma (emergencysituations, before or after surgical treat-ment).

Acute expansion of extracellular fluid volume caused by the os-motic effect of mannitol leads to side effects:-Headache-Nausea-Vomiting-Chest pain– Hyponatremia– Exacerbate congestive heart fail-ure.

-Mannitol not ab-sorbed from GI tract so must be administered IV.-Glycerin and isosorbide are orally active agents.-Ideal osmotic diur.:-Distribute only in vascular fluid compartment-Pharmacologi-cally inert-Not metabolized-Readily filtered at glomerulus-Not reabsorbed from tubules

Loop Di-uretic

FurosemideTorasemideEthacrynic acid

-“High ceiling” diuretics (up to 25% of filtered Na+ load)-Secreted via proximal tubule anion exchanger.-Inhibit Na/K/2Cl symport in thick ascending limb.-Na+ gradient facilitates K+ and Cl- reabsorption via basolateral sym-porter.-K+ re-enters tubule through apical channel while Cl- exits through baso-lateral channel.-Na+ reabsorption in thick ascending limb = 25% filtered load.-⇑ in Na delivery to the distal tubule ⇑ K+ and H+ excretion (hypokalemic metabolic alkalosis).-Increase RBF by stimulating PG syn-thesis (generalized vasodilation)-⇓ NaCl delivery to macula densa cells blocks tubuloglomerular feedback decreased regulation of GFR-Vol loss stimulates renin release and SNSA.

-Congestive heart failure: venodilation decrease preload, alle-viate pulmonary edema, decrease edema-Renal disease (in-cluding acute renal failure & nephrotic syndrome): reduce edema, maintain RBF to preserve GFR-Cirrhosis: reduce edema-Other edematous states: stimulate wa-ter loss

-K+ wasting drug leads to nega-tive side effects-Hypovolemia (hypotension)-Hyponatremia, hypocalcemia, hypochloremic metabolic alkalosis, hypokalemia (cardiac arrhythmias)-Decreased GFR if systemic pres-sure decreases too much-Ototoxicity-Hyperuricemia (gout): due to re-tention of uric acid-Infrequent cases of insulin resis-tance b/c hypokalemia decreases insulin sensitivity, which increases hyperglycemia-Digitalis: Hypokalemia can in-crease digitalis-induced arrhyth-mias.-Glucocorticoids: Inherent miner-alocorticoid activity can induce fluid retention to antagonize di-uretic response, produce additive K+ loss and additive glucose intol-erance.-NSAIDs: Inhibition of renal and vascular prostaglandin production blunts diuretic and vasodilating effects.-Aminoglycoside antibiotics: Augment ototoxicity.-Pharmacokinetic drug interac-tions: 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-choloro-thi-azide

-Only 5% of Na load enters distal tubule.-Inhibit NaCl symporter on luminal membr.-Cl- absorbed against its concentration gradient (exits passively through a ba-solateral channel).-⇑ Na+ delivery to distal tubule ⇑ K+ and H+ loss K+ wasting-⇓ Ca2+ excretion by unknown mech-anism

-Hyponatremia-Volume depletion and hypoten-sion, can decrease RBF and GFR.- Hypokalemia, ⇑ risk for torsades de pointes (prolongation of the QT interval) w/quinidine (compete for anion transporter)-Hypomagnesemia, Hypercal-cemia-Hypokalemia decreased insulin sensitivity, ⇑ LDL cholesterol (con-traindicated in diabetes)

-NOT effective with impaired GFR-Does NOT affect tubulo-glomerular feedback (doesn’t increase renin se-cretion).

Na+ Chan-nel In-hibitors

AmilorideTriamterene

-Inhibit luminal sodium channel of principal cells (ENaC).-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 de-creased Na+ entry.-Reduce H+ secretion, perhaps by in-hibiting Na+-H+ transporter.

-Most serious and potentially fatal side effect is hyperkalemia K+ build-up in plasma-Metabolic acidosis most likely in pts w/ impaired renal function or excessive potassium intake d/t K/H exchange-Potassium supplements are gen-erally not given with these drugs-ACE inhibitors and beta-blockers may exacerbate hyperkalemia.-Decrease Ang II decrease aldos-terone exacerbate hyperkalemia

-Inhibition of H+ secretion may al-kalinize the urine.

Mineralo-corticoid Antago-nists

Spironolac-toneEplerenone

-Binds to & blocks mineralocorticoid R in late distal tubule and early collect-ing duct.-Inhibits mineralocorticoid-dependent retention of NaCl and water and ex-cretion of K+ and H+.-Blocks aldosterone decreased Na/K ATPase activity prevents reabsorp-tion at late tubule-Exerts a Mg2+- and Ca2+-sparing ef-fect by ill-defined mechanisms.-Opposes mineralocorticoid ac-tions:– Activate luminal Na channels (ENaC)– Synthesize new channels (ENaC)– Activate Na/K-ATPase– Increase ATP synthesis

-Can prevent or re-verse hypomagne-semia and hypocal-cemia induced by thi-azides and loopdiuretics.

-Increases Na+ and Cl- excretion and decreases loss of K+ , Mg2+ and H+ Hyperkalemia and meta-bolic acidosis.-Anti-androgenic effects (spirono-lactone) can lead to menstrual ir-regularities andgynecomastia and impotence in males.-Eplerenone avoids anti-andro-genic effects.

-Synthetic steroid-Require endoge-nousaldosterone to be effective

Vaso-pressin An-tagonists:Aquaretics

Conivaptan -Correct hyponatremia by blocking AVP binding to the V2 receptor in lu-minal membrane of collectingduct cells restores plasma [Na+], decreases water permeability, & in-creases free water clearance.- Inhibits ADH-dependent retention of water in collecting duct.

-Used for treatment ofhyponatremia (excessfree water).

-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/ encephalopa-thy, neuropathy, intracranial hemorrhage, aortic dissection, preeclampsia, pulmonary edema, unstable angina, & MI; parenteral therapy re’d – 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 sys-tolic BP 2-4 mmHg after 1 wk)-HTN + Diabetes: ACE Inhibitor + Angiotensin II receptor antagonist slow progression of diabetic nephropathy-HTN + Stable angina pectoris: β blocker or long-acting Ca2+ channel blocker-HTN + Acute coronary syndromes (unstable angina or MI): β blocker and ACE Inhibitor-HTN + Heart failure: β blocker, ACE Inhibitor, & diuretic-HTN + Chronic kidney disease: aggressive BP management; ACE Inhibitor, ARB, loop diuretic-HTN + Hyperthyroidism: use β blocker to prevent the increase in systolic BP & HR

Classification of Hypertension (>18 years of age)Category Systolic Diastolic

Normal <120 <80Prehypertension 120-139 80-89Stage 1 140-159 90-99Stage 2 >160 >100

Drug Class Drug Name Mechanism of Action Uses Toxicities/Side Effects

Diuretic Thiazide di-uretics - Hy-drochloroth-iazide

-Primary mechanism: Blocks the Na+/Cl- co-transporter on the lumi-nal side of the DCT (where 10% of Na+ is reabsorbed) increased ex-cretion of NaCl & H2O & decreased intravascular vol & cardiac output-Secondary mechanism: during chronic therapy, thiazides decrease interstitial fluid & vascular stiffness vasodilation decrease in peripheral resistance

-Low doses are commonly used to treat uncomplicated HTN as monotherapy or in combination w/ other agents -Requires 2-4 weeks to act, so do not use in HTN emer-gencies

-Hypokalemia – due to increased luminal Na+ being exchanged for K+ in the collecting tubule, causing excess K+ loss; complicates ar-rhythmias & 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 intra-cellular 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 al-lergic to sulfonamides-Not effective in pts w/ decreased renal func-tion

Loop diuretic - Furosemide

-Blocks the Na+/K+/2Cl- symporter on thick ascending loop of Henle increased excretion of NaCl & H2O decreased intravascular vol & car-diac output-Decreased import of K+ causes hy-pomagneisa & hypocalcemia by de-creasing transepithelial potential difference that drives paracellular entrance of Mg2+ & Ca2+

-Hypertensive emergencies assoc w/ acute pulmonary edema, acute renal failure, & heart failure

-Same as for thiazides-Also cause calciuria & ototoxicity -Drug interactions: do not use with other drugs that produce ototoxicity (aminoglycoside antibiotics, for ex)

Potassium-sparing di-uretic – Amiloride, Triamterene, Spironolac-tone

-Amiloride & Triamterene Block Na+ channels, preventing exchange w/ K+ in collecting tubule-Spironolactone blocks the aldos-terone receptor, decreasing ex-change in collecting tubule & DCT

-Ameliorate hypokalemia produced by thiazide or loop diuretics

-Hyperkalemia in pts w/ renal disease or those taking ACE inhibitors, angiotensin II receptor antagonists, or beta blockers (B1 receptors work in the kidney)-Spironolactone: gynecomastia, impotence, menstrual problems

α-Adrener-gic Agonist

Clonidine, Methyldopa (α2 selective), Methyloxam-ine, Phenyle-phrine (α1 se-lective)

-Acts on brainstem pressor centers, sensitizing them to inhibition by baroreceptor reflexes reduced NE release presynaptically decreased sympathetic outflow decreased cardiac output & peripheral resis-tance-Autoreceptors limit synaptic trans-mission by inhibiting transmitter re-lease presynpatically

-Substitute drug in cases of poor resistance, side effects, or contraindications to 1st line treatments (thiazide di-uretics, beta blockers, ACE inhib)-Usually used w/ a diuretic-Hypertensive urgencies-Methyldopa is used to treat HTN in pregnancy

-Sedation, depression-Xerostomy (dry mouth)-Sexual dysfunction-Rebound HTN upon abrupt withdrawal; Hy-pertensive crisis must be treated w/ alpha & beta blocker -Drug interactions: tricyclic antidepressants inhibit hypotensive effect & clonidine reduces antidepressant action; rebound HTN upon Clonodine withdrawal

α-Adrener-gic Antago-nist

Prazosin -Decrease peripheral resistance (af-terload) & venous return to the heart (preload)-Reduction in preload reduces car-diac output = little reflex tachycar-dia

-Uncomplicated HTN as a 2nd

or substitute drug-3rd drug in unresponsive pts-Beneficial in pts w/ HTN & dislipidemia, premature ejaculation, or prostatic hy-perplasia (blocks alpha 1 trigone & sphincter smooth muscle relaxation facili-tates micturition)

-Postural hypotension sudden syncope-Fluid retention (avoid though use in combina-tion w/ a diuretic)-Monotherapy can increase CHF-Drug interactions: aggravation of 1st dose syncope when used w/ ACE inhibitor or beta blocker

β-Adrener-gic Antago-nist

Propranolol (non-selective), Metoprolol (cardioselec-tive), Esmolol (short-acting, cardioselective for emergen-cies) ABEAM = Acebutolol, Betaxolol, Es-molol, Atenolol, Metoprolol

-Decrease HR & contractility re-duction in cardiac output-Decrease rennin production de-crease Ang II decrease peripheral resistance & aldosterone secretion less water & Na+ retention-Propranolol (noselective, β1 & β2, full agonist) reduces HR & produces bronchospasm-Metoprolol (cardioselective, β1 at low doses) reduces HR & produces less bronchospasm-Pindolol (nonselective, partial ago-nist) & Acebutolol (cardioselective) have partial agonist actions (intrinsic sympathomimetic activity) & pro-duce less bronchospasm & lipid al-terations

-Uncomplicated HTN as a monotherapy or in combina-tion w/ other agents-HTN complicated by MI, A-V node arrhythmias, mi-graines, hyperthyroidism, and/or compensated heart failure

-Bronchospasm w/ non-selective agents-Bradycardia - aggravation of heart failure in uncompensated pts-Decrease in hypoglycemia recovery in-creased risk for diabetes type II & masking of hypoglycemic signs-Aggravation of peripheral vascular -disease (non-selective agents)-Increase in triglycerides & decrease HDL-Angina & rebound HTN upon withdrawal-Depression, sedation, sleep disturbances, sex-ual dysfunction-Drug interactions: bradycardia & heart block when used w/ voltage-gated Ca2+ channel blockers; hypertensive crisis when used w/ Epi (unopposed stimulation of α1); decreased he-patic clearance when used w/ cimetidine & flu-oxetine

α & β- Adrenergic Receptor Blockers

Labetalol, Carvedilol

-Labetalol – indicated for HTN emergencies (IV) ex-cept acute heart failure-Carvedilol – not commonly used for HTN; used for heart failure

ACE In-hibitors

Captopril,Lisinopril

-Block ACE decrease Ang II & al-dosterone levels vasodilation, less Na+ & H2O retention, decreased K+ loss-Inhibits breakdown of bradykinin increases nitric oxide & prostaglandin levels vasodilation

-1st line therapy for young Caucasian pts-1st line therapy for pts w/ HTN & diabetes, renal fail-ure, myocardial ischemia, or CHF; can be used as monotherapy or in combina-tion w/ diuretic-IV therapy for hypertensive emergencies-Heart failure: controls re-modeling by causing vasodi-lation; decreases mortality

-Increased lung bradykinin levels can cause dry cough & angioedema, leukopenia, loss of taste-Hyperkalemia-Use w/ caution in pts w/ renal failure – use lower dose & monitor K+ & Renal stenosis – marked hypotension, reversible renal dysfunc-tion due to decrease in glomerular filtration in stenotic kidney-Contraindicated in pregnancy – fetal death, kidney failure, malformations-Drug interactions: do not use with K+ spar-ing diuretic d/t hyperkalemia; NSAIDs will pre-vent the increase in prostaglandin levels in-duced by ACE Inhib

An-giotensin II Receptor Anatago-nists (ARBs)

Losartan -Antagonizes A-II receptor de-crease Ang II & aldosterone levels vasodilation, less Na+ & H2O reten-tion, decreased K+ loss-Do not affect bradykinin

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

Ca2+ Chan-nel Antago-nists

Verapamil, Diltiazem, Nifedipine / Dihydropyri-dines

-Inhibit VSM contraction -2nd or 3rd line therapy -Useful in emergencies-1st line therapy in elderly & African American pts-Pts w/ comorbid conditions such as angina, atrial fibrilla-tion, & Raynaud’s syndrome-Not effective as monother-apy b/c of physiologic com-pensatory response: ↓ sys-temic vascular resistance & arterial pressure activates RAS & sympathetic outflow ↑aldosterone, ↓ renal Na+ excretion ↑ plasma vol, peripheral resistance, & CO compensatory ↑ in BP

-Exacerbate CHF, fluid retention-Excessive depression of SA & AV nodes (in pts w/ ventricular tachycardia = ventricular fibrilla-tion & hemodynamic collapse)-Decreased heart contractility bradycardia-Constipation d/t intestinal smooth muscle re-laxation-Short-acting dihydropyridines can increase risk of MI by decreasing BP too quickly-Drug interactions: combined IV admin of ve-rapamil & a beta blocker can result in asystole; heart block can occur when combined with dig-italis toxicity

Direct-act-ing Va-sodilators

Arterial – Hy-dralazine, Mi-noxidil

-Decrease peripheral resistance (af-terload) by increasing K+ channel opening, causing hyperpolarization or VSM

-3rd drug in unresponsive pts-HTN in pts w/ eclampsia-Usually used in combination w/ a beta blocker (to prevent reflex tachycardia) & a di-uretic (to prevent fluid re-tention)-Heart failure (BiDil)

-Lupus-like syndrome-Tachycardia-Aggravates angina-Fluid retention

Arterial & ve-nous – Ni-trates (Nitro-glycerine, Dini-trate isosor-bide), Sodium nitroprusside

-Predominantly relax veins (& arter-ies), decrease preload & afterload, & dilate coronary arteries-Act as nitric oxide donors stimu-late guanylyl cyclase increase cGMP activate PKG decrease cy-toplasmic Ca2+ levels & activate myosin light chain phosphatase smooth muscle relaxation

-Hypertensive emergencies assoc w/ acute pulmonary edema, myocardial is-chemia, & aortic dissection-Treats angina, ischemic HD, & heart failure (in combina-tion w/ hydralazine)-Treatment of cyanide poi-soning produces methe-moglobinemia leads to transfer of cyanide from mi-tochondria to circulation

-Orthostatic hypotension-Reflex tachycardia-Headache, increased intracranial pressure-Tolerance-Fluid retention (d/t increase in aldosterone)-Methemoglobulinemai (Hb w/ ferric iron) at toxic doses (useful in treatment of cyanide poi-soning)-Drug interactions: hypotension when used e/ sidenafil

HEMOSTATIC & THROMBOSIS DRUGS

Drug Class

Drug Name Mechanism of Action Uses Toxicities/Side Effects Pharmacokinetics / Notes

Antico-agu-lant

Heparin -Catalyzes activation of an-tithrombin III Binds to endothe-lium & antithrombin III inhibits activated coagulation factors thrombin (IIa), plasmin, Xa, IXa, Xia, XIIa, and kallikrein

-Immediately sup-press blood coagula-tion in thromboem-bolic disorders (PE, stroke, angina, MI, DVT)-Can be used during pregnancy (doesn’t cross placenta

-Bleeding, thrombocytopenia, osteo-porosis-Heparin-Induced Thrombocytope-nia (HIT): type 1 caused by heparin in-teracting w/ platelets leading to low platelet aggregation (non-immune); type 2 causes pt to develop thrombi & is d/t IgG antibody against PF4-hep-arin complex (immune form)-Reversal in the OR w/ protamine sulfate

-IV or SubQ – not ab-sorbed from GI tract-Negatively charged & binds to plasma pro-teins-Must perform blood coagulation tests - aPTT

Low Molecu-lar Weight Heparin – Enoxaprin, Dalteparin,

-Same as heparin but with a greater capacity to potentiate fac-tor Xa inhibition by antithrombin than thrombin (chains too short to bridge antithrombin to thrombin)-Inhibits Xa>IIa

-Anticoagulation -Risk of bleeding-Lower risk of osteoporosis-Less effect on platelet function – less inhibited by platelet factor IV (de-creased likelihood of an immune re-sponse)-Not as easily reversible

-Longer ½ life-Better bioavailability-SubQ admin-No monitoring neces-sary

Warfarin (Coumadin), Dicumarol

-Blocks the gamma carboxylation of glutamine residues in all the vi-tamin K dependent clotting fac-tors: prothrombin, factors VII, IX, X, protein C-Anticoagulation effect seen in 24 hrs, so initiate w/ heparin or direct thrombin inhibitors

-Chronic anticoagu-lation (not for rapid anticoagulation – may take a few days for clinical effect)-For thromboembolic disease & ischemic stroke in pts w/ atrial fibrillation

-Significant drug interactions-Risk of bleeding: increases w/ age, renal failure, recent trauma or surgery, prior hx of bleed, HTN, drug interactions-99% plasma protein bound drug in-teractions-Efficacy decreased by increased lev-els of Vit K in diet, liver disease, broad spectrum antibiotics-Warfarin-induced skin necrosis-Fetal toxic (contraindicated in preg-nancy)-Use w/ caution in HIT & DVT pts in-duce limb gangrene (insufficient pro-tein C)-Must monitor INR levels

-1/2 life ranges from 25-60 hrs (long!)-Duration of action for a single dose is 2-5 days-Reversal w/ Vit K-Cytochrome P-450 metabolism-Follow PT/INR levels - Increases PT

Indirect Thrombin Inhibitor

Fonda-parinux

-Synthetic pentasaccharide w/ se-lective antifactor Xa activity-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

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

Danaparoid -AT-dependent anticoagulant w/ predominant antifactor Xa activity

-Can be used to treat pts w/ HIT

-Not reversible by protamine sulfate -Plasma ½ life of 24 hrs-Renal clearance

Direct Thrombin Inhibitors

Hirudin, Lepirudin

-Inactivates bound fibrin with ac-tion independent of antithrombin III & little effect on platelets-Not inactivated by antiheparin proteins

-Use as an alterna-tive to heparin for anticoagulating pts w/ HIT

-Produced in the sali-vary gland of leech

Argatroban -Synthetic L-arginine derivative that acts as a competitive in-hibitor of thrombin (thrombolytic)

-Prophylaxis of HIT-Drug of choice for pts w/ renal impair-ment

-Cleared by the liver-IV admin – t1/2 = 45 min

Ximelaga-tran

-Dipeptide that mimics the throm-bin binding site of fibrinopeptide A (thrombolytic)

-Can increase alanine aminotrans-ferase levels (reversible)

-Lipophillic prodrug of melagatrain-Oral admin-Kidney excretion

Protein C Drotrecognin alpha

-Recombinant form of human acti-vated Protein C that inhibits coag-ulation by proteolytic inactivation of factors Va & VIIIa-Anti-inflammatory effects

-Prevents death d/t sepsit if given within 48 hrs of onset of or-gan failure

-Bleeding

Thrombo-lytics

Alteplase (t-PA), Uroki-nase

-Derived from recombinant hu-man tissue plasminogen activator & works as a plasminogen activa-tor-Converts plasminogen to plasmin by directly hydrolyzing the argi-nine-valine bound in plasmino-gen; plasmin degrades fibrin & fibrinogen as well as the procoag-ulant factors V & VIII-Activity dependent on presence of fibrin

-Uses: lysis of acute pulmonary throm-boembolism or acute coronary arterial thromboembolism assoc w/ evolving MI-Clot-specific action (does not cause a lytic state)

-Contraindicated in pts w/ severe HT, hx of bleeding, recent surgery

-Parenteral

Streptoki-nase, AP-SAC

-Nonspecific plasminogen activa-tor (circulating & bound) indi-rect action by forming a noncova-lent compound w/ plasminogen-Induces procoagulant response via increased release of thrombin

-Uses: acute MI, pul-monary embolism, DVT, occluded arteri-ovenous cannulae, & acute arterial throm-bosis & embolism

-High potential for antigenicity-Contraindicated in pts w/ severe HT, hx of bleeding, recent surgery

-Rarely used

Antifib-rino-lytic

Aminocaproic Acid

-Inhibits fibrinolysis -Can treat throm-bolytic toxicity

Antiplate-let / An-tithrom-botic

Aspirin -Acetylates irreversibly inhibit cy-clooxygenase to prevent conver-sion of arachidonic acid to throm-boxane A2 (TXA2) prevents platelet aggregation increase bleeding time

-Antipyretic-Analgesic-Anti-inflammatory-Antiplatelet drug

-Gastric ulceration-Bleeding-Hyperventilation-Reye’s syndrome-Tinnitis (CN VIII)

-No effect on PT, PTT

Ticolpidine, Clopidogrel

-Irreversibly block ADP receptors prevents glycoprotein IIb/IIIa ex-pression inhibits ADP-induced binding of fibrinogen to platelet membrane inhibits platelet ad-hesion-Affects blood viscosity & reduces fibrinogen concentration

-Uses: completed strokes, unstable angina, transient is-chemic attacks, acute coronary syn-drome, coronary stenting

-GI disturbance, Hemorrhage, Leukopenia, neutropenia, TTP, BM tox-icity

-Req blood testing for 1st 3 mos

Cilostazol, Dipyri-damole

-Inhibit phosphodiesterase (PDE) type III prevents the breakdown of cAMP increases cAMP levels in platelets increases vasodila-tion & inhibits platelet aggrega-tion

-Cilostazol is used to treat intermittent claudication-Decrease triglyc-erides & increase HDL cholesterol

-Used with aspirin

Abiciximab -Noncompetitive inhibitor / mono-clonal antibody to GPIIb/IIIa recep-tor on activated platelets pre-vents binding of vWF blocks platelet plug formation (fibrin binding) & aggregation

-Thrombotic arterial disease-Unresponsive un-stable angina-Reduce risk of MI

-Bleeding-Thrombocytopenia

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