Pharm_Merged Flashcards
What non-drug item can increase the risk of statin adverse events?
Grapefruit juice
What is the function of chylomicrons?
Exogenous lipoprotein: Transport of dietary fat, cholesterol and bile acids from intestine to liver
What is the route of administration for all thrombolytic agents?
IV
Describe the elimination of beta blockers
Liver: Propranolol, carvedilol, metoprololKidney: atenolol, nadolol, sotalol
What is the difference between mexiletine and lidocaine?
Mexiletine is an orally active lidocaine analogue with a much longer half life-Used off label for chronic pain
What are the side effects of verapamil and diltiazem?
Bradycardia
CHF
Heart block
Hypotension
What are the actions of cAMP in cardiac muscle?
Opens L-type Ca2+ channels
Increased reuptake of Ca into SR
Increased pacemaker current
Increased rate of conduction
Where in the body are nitrates most effective?
Systemic circulation
What is the mechanism of action of lomitapide?
Inhibition of MTP enzyme, preventing the formation of chylomicrons by enterocytes and VLDLs by hepatocytes
What is the mechanism of action of eplerenone?
Aldosterone antagonist
What are the factors that limit fibrinolysis?
Fibrin crosslinking by factor XIIIa Antiplasmin content in and around fibrin clot
Is warfarin plasma bound?
Yes, 97% bound to albumin This gives warfarin a long half life
What are the products of platelet activation and endothelial interaction?
Prostaglandin derivatives
Endoperoxides
Thromboxanes
Which thrombolytic agents are used for pulmonary embolism?
Streptokinase and urokinase
What are the most commonly used beta blockers?
Metoprolol Atenolol
What transporter is responsible for liver uptake of statins?
OATP2
Where do diuretics have to get to in order to be effective?
They must reach the tubular fluid in order to be effective
What is the only cholesterol absorption inhibitor drug?
Ezetimibe
What is the affect of arginine analogs (ex: NMMA)?
Inhibition of the conversion of arginine to citrulline decreases formation of NO
What is the typical non-selective beta blocker?
Propranolol
What are the contraindications for mannitol?
CHF, renal failure, pulmonary edema *CHF and RF reduce glomerular filtration, pulmonary edema would be exacerbated
Describe the pharmacokinetics of amiloride
Long half life (21h) Secreted into tubule via OBTExcreted unchanged by kidney
What are the side effects of all beta blockers?
Bradycardia
Impotence
Increased TGs
Decreased HDLs
Hyperglycemia
Impaired exercise tolerance
What is the mechanism of action of the statins?
HMG-CoA reductase inhibitors Competitive inhibition of the rate limiting enzyme of cholesterol biosynthesis. SREBP is activated leading to increased LDLR gene expression, increased LDL clearance
What is the difference in vasodilator drugs used for acute versus chronic CHF?
Acute CHF drugs (nitroprusside, nitroglycerin) are given IV and have rapid onset of actionChronic CHF drugs (ACEi’s, ARBs, hydralazine, minoxidil, prazosin, LCZ696) are given orally and have slower onset of aciton
What are the contraindications for fibrate usage?
Pregnant/lactating women Hepatic dysfunction (drug is hepatotoxic) Renal dysfunction (drug renally excreted) Gall bladder disease
Describe the pharmacokinetics of spironolactone
Slow onset, takes days for effect Liver metabolism to several active metabolites
How does the Ca2+ reabsorption differ between loop diuretics and hydrochlorothiazide?
Loop diuretics decrease Ca2+ reabsorption whereas hydrochlorothiazide increases Ca2+ reabsorption
What are the main factors that promote fibrinolysis?
Plasminogen content of clot
tPA content/activity in and around clot
Protection of bound plasmin from antiplasmin
How does glutathione affect vascular pathology?
In CVD and DM, glutathione levels are reduced. This leads to increased vascular pathology due to increased NO.
What are the side effects of ivabradine?
Luminous phenomena, bradycardia, AV block
List the class IB anti-arrhythmic drugs
Lidocaine Mexiletine
Describe the population variation of clopidogrel and prasugrel
Prasugrel has less population variation than clopidogrel. A significant portion of the population is non-respondant to clopidogrel due to a polymorphism.
What levels of LDL and TG are considered “very high”?
LDL > 190 mg/dLTG > 500 mg/dL
What are the clinical indications for spironolactone?
Primary and secondary hyperaldosteronism
Liver cirrhosis (drug of choice)
Hypertension
What are the mechanical effects of digitalis glycosides?
Increased contractility-increased velocity of shortening, force of contraction, ventricular emptying-Decreased ESV and EDV
Contraindications of ACE inhibitors
Pregnancy
Bilateral renal stenosis
Describe the contents of light and dark granules
Light: PF4, beta-thromboglobulin, PDGF
Dark: Ca2+, Serotonin, ATP/ADP
Describe the effect of gain of function and loss of function mutations in the PCSK9 gene
Gain of function: high LDL levels, increased risk for CVD
Loss of function: low LDL levels, decreased risk for CVD
How does hepatic cirrhosis cause systemic edema?
Increased pressure in sinusoids leads to exudate, ascites Decreased albumin production decreases oncotic pressure, RAA system activated, Na retention
What is the major danger of anti-arrhythmic drugs?
The do not act specifically, and can end up depressing conduction in normal cells leading to drug-induced arrhythmias -Dosage, HR, acidosis, electrolytes and ischemia all impact the effect
Diuretics primarily prevent Na+ ________________
Diuretics primarily prevent Na+ entry into the tubule cells
What is the mechanism of action of bile acid-binding resins?
Bind to negatively charged bile acids to prevent small intestinal reabsorption, thus leading to excretion of bile acids via feces. Increased bile acid production –> decrease cholesterol levels
LDLR is upregulated leading to increased LDL clearance
What are the clinical uses of heparin?
Therapeutic, surgical and prophylactic ANTICOAGULATION Unstable angina Adjunct therapy with thrombolytic drugs Thrombotic and ischemic strokes
What are the side effects of nitrates?
Exaggeration of therapeutic effects: -orthostatic hypotension-reflex tachycardia-headacheTolerance can also develop
What is ranolazine?
New class of antianginal drugs with a unknown mechanism
Inhibits pFOX, decreasing beta oxidation
What are the adverse effects of amiloride?
Hyperkalemia (exacerbated by NSAIDs)GI upset: NVD Muscle cramps CNS: headache, dizziness
What is acutely decompensated CHF?
Acute CHF superimposed on the setting of chronic CHF
Which CCB has the strongest negative inotropic and chronotropic effects?
Verapamil has the strongest inotropic and chronotropic effects
How are statins excreted?
ALL statins are excreted via bile and feces after glucoronidation by UGT1A1/1A3 in the liver
Describe the effect of metoprolol on exercise performance
Decreases variation in heart rate and reduces ischemic changes in response to exercise
What lab test is used to monitor warfarin therapy?
PT is used to monitor warfarin and its effect on the extrinsic pathway
What are the causes of hyperlipidemia?
Genetics: familial genetic disorder
Lifestyle: diet, obesity, alcohol, smoking, age, physical inactivity
Diseases: T2 DM, hypothyroidism
Drugs: antiviral, antipsychotics, corticosteroids, oral contraceptives
What are the ions secreted in the collecting ducts?
K+ and H+ are secreted in the collecting ducts
How is thrombolytic therapy useful for MI patients?
Many MI patients have thrombi formed in the coronary vessels. Thrombolytic therapy is used to try to get rid of the fibrin-rich occlusion
What are the interactions with anti-Xa drugs?
Anti-Xa drugs are potent CYP3A4 inhibitors
What are the indications for dronedarone?
Atrial fibrillation/flutter
Which diuretic drugs most profoundly increase urinary K+?
Loop + thiazide combo
What are the non-pharmacological therapies for acute CHF?
PCI/surgical therapy: revascularization and/or valve repair
Ultrafiltration
Intra-aortic balloon pump
Ventricular assist devices
Location of action of acetazolamide
Proximal convoluted tubule
What are the non-pharmacologic anti-arrhythmic therapies?
Vagal maneuvers
Radiofrequency ablation/Cryoablation
Electrical cardioversion
Implantable cardioverter-defibrillators
Describe the cardiac conduction system
The sinoatrial node is the pacemaker, and is located in the wall of the right atrium. The SA stimulus spreads across the atria to the AV node, which has a 150ms delay. The his-Purkinje system then rapidly depolarizes the ventricles leading to cardiac contraction
What is bivalirudin?
A synthetic antithrombin that is a combination of hirudin and a tripeptide used for anticoagulation during stent placement and angioplasty
What are the contraindications for bile acid resins?
Type III dysbetalipoproteinemia Raised TGs (risk for pancreatitis)
What is the mechanism of action of the beta blockers?
Decreased 1) cardiac contractility 2) Cardiac Output3) renin secretion
Major side effect of diltiazem
Bradycardia
What is the function of plasmin?
Plasmin is the major fibrinolytic enzyme. Breaks down fibrinogen and fibrin.
What are the indications for beta blockers?
Prevent recurrent infarct, sudden death after MI
Exercise-induced arrhythmias
AFib, AFlutter, AV nodal reentry
What is the mechanism of action of mipomersen?
This oligonucleotide reduces the expression of apoB leading to reduced production of VLDLs by hypatocytes
What is the indication for Ciostazol?
Management of intermittent claudication
What are the adverse effects of procainamide?
Ganglion blocking properties
Hypotension
Anticholinergic effect
Induce torsade de pointes
Lupus erythematosus syndrome from chronic use (30% of patients)
Clinical use of nitrates
Angina pectoris
Hypertensive emergencies
CHF
What are the drugs that treat hypertriglyceridemia?
Niacin
Fibrates (gemfibrozil, fenofibrate)
What are the drug interactions for potassium sparing diuretics?
NSAIDs ACE inhibitors with ARBs
What are the adverse effects of lidocaine?
Least cardiotoxic Class I drug Can cause hypotension Local anesthetic properties: paresthesias, tremors, nausea, lightheadedness, hearing disturbances, slurred speech, convulsions
What regulates the H2O permeability of the collecting duct?
In the presence of ADH, the collecting ducts are permeable to H2O due to aquaporin insertion
What drugs are vasodilators used for treating HTN?
Hydralazine Minoxidil Nitroprusside
What is the major action of angiotensin II?
Profound vasoconstriction
Which antiplatelet drugs must be given via IV?
The GP IIb/IIIa inhibitors are the only antiplatelet drugs not given orally
Describe the function of vasoactive intestinal peptide
VIP causes vasodilation and also functions as a neuromodulator
Describe the mechanism of action of niacin
COMPLEX-decreases release of FFAs, decreasing FA synthesis-increases HDL via increased apoA1-decreased macrophage recruitment to lesions-decreased thrombosis risk by decreasing Lp(a)-decreased VLDL production, increased clearance
What are the treatment objectives for acute CHF?
Early recognition and treatment Decrease symptoms - Reduce pulmonary congestion: loop diuretics, venodilators, nesiritide-Increase CO: –Increase contractility: beta blockers, phosphodiesterase inhibitors –Reduce afterload: nitroprusside
What is the mechanism of action of the loop diuretics?
Block the Na/K/2Cl cotransporter which increases urinary water, Na, K, Ca, and Mg excretion- Also dilates venous system and renal vasodilation mediated by PGs
What are the clinical indications for furosemide?
Acute PE Edema w/ CHF Acute hypercalcemia, hyperkalemia Hypertension
What are the NO levels in septic shock?
NO levels are markedly increased in septic shock.LPS induces NOS-2 to produce NO, leads to hypotension and shock
Mechanism of action for Losartan
Angiotensin II receptor blocker Mediates vasoconstriction and sodium retention
Describe the ionic movements in the distal convoluted tubule
Transporters: lumenal Na/Cl symporter, basolateral Na/K ATPase and Na/Ca antiporter
Na gradient drives Na/Cl symporter-Ca absorption regulated by PTH
Are Calcium channel blockers used for CHF patients?
No. Contraindicated for CHF due to negative inotropic effects
What class of drugs does dabigatran interact with?
Proton pump inhibitors
How do ACE inhibitors affect renal function in diabetics?
Preserve renal function
What is the ECG manifestation of treatment with amiodarone, dronedarone, and sotalol?
QT prolongation on the EKG
What are the clinical indications of amiloride?
Edema Hypertension Used in combo with other diuretics to minimize K+ loss
What is the effect of excessive production of angiotensin II?
Hypertension and disorders of hemodynamics
What is the route of administration for warfarin?
Oral
What are the general pharmacological strategies used to treat hyperlipidemia?
Decrease in LDL (Primary targets) Increase HDL (secondary) Decrease TG (secondary)
What are the main regulators of prostacyclin and thromboxane synthesis?
Endothelial lining Lipoproteins and other blood components Diet, drugs, hemodynamics
How is heparin therapy monitored?
Heparin therapy is carefully monitored using APTT Target APTT is 2-2.5x baseline
What are the indications for the anti-Xa drugs?
Stroke prevention in AFib patients
Prophylaxis of DVT
Where is ACE primarily located in the body?
On the luminal structure of the endothelial cells throughout the vasculature
What is the mechanism of action for mannitol?
Osmotic diuretic (holds water in tubule) that acts in the water permeable segments of the nephron (proximal tubule, descending loop, collecting ducts +ADH)
What are the drug interactions with thrombolytic agents?
Antiplatelet drugs, heparins and dextrans
What are the side effects of potassium sparing diuretics?
Hyperkalemia Gynecomastia
How is heparin metabolized?
25% excreted in urine Some metabolized in liver by heparinases Mast cells take up heparin Endothelium binds heparin
Warfarin is an analogue of _________
Vitamin K Warfarin and Vit K have similar chemical structures
What is the indication for dabigatran?
Stroke prevention in AFib patients
What are the clinical uses of LMW heparin
DVT: Prophylaxis and treatment Acute coronary syndromes management Anticoagulation during procedures
What is the difference between clonidine and guanfacine?
Guanfacine has a longer half life, less chance for rebound hypertension
What are the 4 major vasoactive peptides that have important roles for regulating hemodynamics?
Angiotensin Kinins Endothelins Vasopressin
How do thiazide diuretics cause hypercalcemia?
Inhibition of Na/Cl cotransporter decreases intracellular [Na+], producing a bigger gradient for the Na/Ca antiporter on the basolateral membrane. More Ca gets pumped out of the cells (reabsorption), leading to hypercalcemia
What is the treatment for severe hypercholesterolemia?
Drug therapy: reduce LDL using a statin in order to decrease risk of atherosclerosis
What are the clinical advantages of LMW heparin
Better bioavailability, longer duration of action, less bleeding, lesser thrombocytopenia
What are the thiazide drugs other than hydrochlorothiazide and how to the differ?
Chlorothiazide: 1/10 potency, short half life
Metolazone: 10x potency, long half life
Indapamide: 20x potency, longer half life, liver metabolism
Chlorthalidone: same potency, Longest half life
Describe the pharmacology of omega 3 fatty acid
Contains acids that compete with AA in the PG pathway in order to inhibit the effects of TXA2
What drug interactions are associated with loop diuretics?
NSAIDs Aminoglycosides
What are the main side effects of warfarin?
Bleeding due to hypoprothrombinemia (ecchymoses, purpura, hematuria, hemorrhage)
What is argatroban?
A synthetic anti-thrombin agent used as an anticoagulant alternative to heparin for patients with heparin induced thrombocytopenia
What additional risk must be considered for diabetic patients taking beta blockers
Masked hypoglycemia Epinephrine is released when glucose is low, but its effect is blocked so the typical hypoglycemic symptoms may not present
What are antithrombin concentrates clinically used for?
Congenital antithrombin deficiency Sepsis and DIC
Describe the formation of atherosclerosis starting with endothelial injury
Endothelial injury allows LDL to enter vessel wall. LDL is oxidized and then taken up by macrophages, which convert to foam cells that promote SMC migration and proliferation as well as ECM synthesis. Foam cells release debris leading to fatty streak formation.
How do loop and thiazide diuretics cause metabolic alkalosis?
Lumen negative potential (increased Na and Cl-) enhances H+ efflux from the intercalated cells. More HCO3- is therefore reabsorbed, leading to alkalosis
What are the adverse effects of beta blockers?
Bradycardia, reduced exercise capacity, heart failure, hypotension, AV block Bronchospasm Lowered glucose, lowered HR
What effect do inducers of CYP3A4 have on statin therapy?
Inducers of CYP3A4 reduce plasma concentrations and thus reduce clinical efficacy of statins
What is the main loop diuretic?
Furosemide (Lasix)
When is methyldopa most often prescribed?
Pregnancy with hypertension
What drugs interact with anti-platelet drugs?
Thrombolytic agents Heparin/LMW heparin/Oral anticoagulants Warfarin Antithrombin agents
What is the mechanism of action of heparin?
Inhibits action of Xa, IIa, XIIa, Xia (2,10,11,12) by binding to ATIII and increasing ATIII affinity for these factors
What is the metabolite of procainamide?
NAPA, which has class III activity
What is the mechanism of action of icatibant?
B2 receptor inhibitor May be useful for hypotension and myocardial hypertrophy
What are the therapeutic uses of vitamin K?
-Antidote for drug-induced hypoprothrombinemia -Intestinal disorders and surgery -Hypoprothrombinemias in newborns
Describe the interaction between sildenaphil and nitrates
Strong adverse reaction that can cause severe hypotension. Both drugs result in increased cGMP levels leading to relaxation
What is the mechanism of action of sildenafil (viagra)?
Inhibition of phosphodiesterase Increases cGMP levels (by preventing conversion to GMP) leading to increased relaxation
What condition worsens adverse effects associated with mannitol?
AEs predominate if filtration is impaired because mannitol cannot reach the tubule without filtration
What is the effect of urotensin?
Vasoconstriction of arterial bedsIncreased in patients with end stage heart failure
Describe the mechanism of action of nitrates
Nitrates cause endothelium independent smooth muscle relaxation by activating GC to increase cGMP, dephosphorylates myosin light chains Decreased venous return, decreased LV wall tension, reduced afterload and direct coronary artery vasodilation
What are the 4 major classes of drugs that reduce LDL levels?
Statins Bile acid-binding resins Cholesterol absorption inhibitors PCSK9 inhibitors
What are the endogenous modulators of heparin action?
ATIII Heparin cofactor II Tissue factor pathway inhibitor (TFPI) Platelet factor 4 (PF4)
Which drugs are the ADH antagonists?
Demeclocycline: tetracycline antibiotic Lithium: psych drug for mania Vaptans
What are the loop diuretics other than furosemide and how do they differ?
Bumetanide (40x potency, shorter half life, liver metabolism) Torsemide (longer half life, duration, better oral absorption, liver metabolism) Ethacrynic acid (different structure, used w/ hypersensitivity, BAD AEs)
In addition to ACE inhibitors blocking Ang II production, what other peptides are inhibited?
Bradykinin metabolism is blocked by ACE inhibitorsLeads to hypotension
Which direction does the concentration gradient favor for Na+, Ca2+ and K+?
Na+: InCa2+: InK+: Out
What are the drug interactions for thiazides?
NSAIDs and beta blockers
What adverse effects are associated with amiodarone?
Bradycardia and heart block Pulmonary toxicity, hepatic toxicityPhotodermatitisCorneal microdepositsBlocks T4 to T3Hypo/hyperthyroidisms
What are the side effects of nifedipine?
Reflex tachycardia: major adverse effectPeripheral edemaHypotension
Describe the ionic movements in the thick ascending limb
Transporters: Na/K/2Cl cotransporter moves cations in from lumen, Na/K ATPase basolateral, K+/Cl- cotransport basolateral 1) ATPase maintains Na gradient to drive NaKCl cotransporter 2) K+ enters from both sides and diffuses back into lumen through channel creating a positive lumenal charge 3) Positive lumenal charge repels Mg and Ca promoting paracellular diffusion
What is the difference between amiodarone and dronedarone?
They are structural analogs, but dronedarone does not have iodine atoms attached
What is the effect of calcitonin gene related peptide (CGRP)?
Hypotension and tachycardia
Do PCSK9 inhibitors work if statins are also being used?
Yes. They decrease serum LDL even in the presence of maximally tolerated statin drugs.
What enzymes synthesize NO?
Nitric oxide synthase family of enzymes (three isoforms)
What drugs interact with loop diuretics
Aminoglycosides Anticoagulants (increased effect)Beta blockersDigoxinNSAIDsQuinidineSulfonureasSteroids
Describe the adverse events associated with statins
The most serious adverse effects are muscular: rhabdomyolysis, myalgia, myopathy Others:GI disturbances, Liver enzyme increase,T2DM
What are the CA inhibitors other than acetazolamide?
Dichlorphenamide: 30x potencyMethazolamide: 5x potencyDozolamide: topical ocular use
How do loop and thiazide diuretics cause hypokalemia?
Increased tubular Na+ and Cl- creates a more negative lumen potential, which promotes K+ efflux from principal cells
What is a contraindication for dabigatran?
Renal failure Dabigatran is 100% cleared by the kidney
What diuretic therapies are recommended for CHF?
Spironolactone to prevent hypokalmeia induced heart problems ACE inhibitors (increase K) may be used with thiazide or loop diuretics
Why are vasodilators beneficial for CHF patients?
Reduced afterload due to reduced systemic vascular resistance allows for increased SV and CO
What is the mechanism of action of acetazolamide?
Reversibly inhibits carbonic anhydrase, thus inhibiting the reabsorption of HCO3- in the proximal tubule
What is the most common side effect of heparin and related drugs?
Bleeding
What is the mechanism of action of clopidogrel?
Selective inhibition of the ADP receptor, leading to inhibition of platelet aggregation
What adverse events are associated with fibrates?
Gallstones Myopathy, Rhabdomyolysis
What are the vaptans and how do they differ?
V2 (kidney) receptor antagonists: tolvaptan, mozavaptan, lixivaptanV1a (vascular smooth muscle) and V2 antagonist: conivaptan
Describe the dose dependence of statins
Decreases in LDL are dose dependent, but there larger doses increase adverse events more than they improve therapeutic effect
What specific beta blockers are used for chronic CHF therapy?
Carvedilol Metoprolol Bucindolol
What are the clinical applications of antiplatelet drugs?
Cerebrovascular disease (TIA, stroke) Coronary artery disease (MI, unstable angina) Saphenous vein coronary artery bypass grafts Peripheral vascular disease Small vessel disease Prevention of thrombosis on artificial surfaces
What are the adverse effects associated with mannitol
Caused by increased plasma osmolarity, water leaves cells, Na follows -Acute pulmonary edema -Dehydration -Headache, nausea, vomiting
What are the clinical indications for hydrochlorothiazide?
Hypertension CHF Prevent kidney stones by reducing Ca2+ excretion
What are the main NO donor drugs?
Nitroglycerine Hydralazine L-Arginine
Why doesn’t adenosine kill patients?
It has an extremely short half life, so its effects are short lived
What drugs interact with Thiazides?
Anticoagulants (decreased effect) Beta blockers Carbamazepine Digoxin NSAIDs Quinidine
What are the major thiazide diuretics?
Hydrochlorothiazide Chlorthalidone
What are the contraindications for statin therapy?
Pregnancy, nursing mothers and women who may become pregnant Patients with liver disease
What inotropic agents are used to treat CHF?
Beta agonists: dobutamine, dopamine, isoproterenol and norepinephrine Phosphodiesterase inhibitors: inamrinone, milrinone *These drugs increase cAMP levels
How is BP affected by NO levels?
Decreased NO levels may result in an increased BP
What are the indications for verapamil?
Lowers heart rate and increases PR interval Used for supraventricular arrhythmias (drug of choice) Re-entry arrhythmias/tachycardias Slowed ventricular rate in atrial flutter/fibrillation
What is the route of administration of heparin?
IV or subcutaneous Not absorbed orally or rectally
What is the mechanism of action of the fibrates?
Ligands for the PPAR-alpha transcription factorPromotes expression of genes involved with lipoprotein structure, function and metabolism
What is the effect of dipyridamole?
Coronary vasodilatation
What coagulation factors does warfarin act on?
II, VII, IX, X
What adverse events are associated with ezetimibe?
Flatulence and diarrhea
What is the function of angiotensinase?
Breaks down angiotensin II and III into small fragments
What are the major ionic fluxes associated with each phase of the action potential?
Phase 0: Na and Ca inPhase 1: Transient K outPhase 2: Plateau from Ca2+ inPhase 3: K+ outPhase 4: resting membrane (K+ permeable, but K in = K out)
What are the bile acid binding resin drug names?
Cholestryramaine Colestipol Colesevelam
What is a unique side effect of nitroprusside?
Cyanide poisoning
What are the 3 subclasses of class I antiarrhythmic drugs and how do they differ?
IA: intermediate kinetics, APD prolonged IB: fast kinetics, APD decreased IC: slow kinetics, APD unchanged
What is the clinical effect of omega-3 fatty acids?
Lowers TG levels, increases HDL, may increase LDL
What is Bosentan?
A non-selective ET antagonist available orally and IV Inhibits endothelin
What drugs interact with bile acid resins?
Many. Do not give drugs at same time as resins (Stagger doses to avoid interactions)
What are the activators of plasmin?
t-PA, urokinase, streptokinase Factor XIIa
Describe the composition of lipoprotein particles
Lipid membrane made of phospholipids and cholesterol Hydrophobic core containing TGs and cholesterol esters Apolipoproteins, structural proteins and ligands for particle uptake
How do CA inhibitors cause hypokalemia?
Increased tubular HCO3- makes lumen potential more negative. This electrogradient increases K+ efflux from principal cells into the tubule and thus increased K+ excretion, hypokalemia
How does diuretic treatment differ between chronic right heart failure and acute left heart failure?
Right: oral loop diuretics Left: IV loop diuretics (Emergent situation)
What are the two pathways of arachadonic acid metabolism?
Cyclooxygenase pathway to form PGs Lipoxygenase pathway to form LTs
What are the major natriuretic peptides?
ABC: Atrial NP Brain NP C-type NP
What is the difference between prazosin, terazosin, and doxazosin?
Terazosin and doxazosin have longer half lives than prazosin
What effect does NO have on platelet function?
NO is a potent inhibitor of platelet adhesion, activate and aggregation NO also regulates release of 5HT, growth factors and TXA from platelets
What pharmacological changes are beneficial in order to correct cells with abnormal automaticity?
Reduced phase 4 slopeIncrease max EmIncrease threshold potentialIncrease action potential durration
What channels/receptors are affected by propafenone?
Potent Na+ channel blocker Also blocks K+ channels Weak beta blocking activity
What class of drugs does warfarin belong to?
Vitamin K antagonists (VKAs)
Describe the pharmacokinetics of mannitol
Not orally absorbed, so given IV to reach kidneyHalf life is 1.2 h
What is fondaparinux?
Pentasaccharide Complexes with ATIII in order to inhibit factor Xa Used for management of DVT
Compare the clinical benefits of angiotensin receptor antagonists and ACE inhibitors
They are basically identical: decreased function of angiotensin II
What commonly precipitates rhabdomyolysis in patients taking statins?
High statin dose OR drug interaction Drugs that inhibit CYP3A4 (cyclosporins, macrolides, ketaconazole)
Describe the role of kinins in pain
Promote redness, local heat, swelling and painPain is produced via nociceptive afferents in the skin and viscera
What are the major adverse effects associated with niacin?
Skin flushing, itching Inhibited uric acid secretion can cause gout Can exacerbate peptic ulcer disease
Compare the potency of kinins to histamine
Kinins are 10x more potent than histamine
What factors effect the dose of oral anticoagulants?
Nutrition, anemia, liver disease, biliary obstruction, drugs
What are the main effects of thrombolytic therapy?
Reduce thrombus size Reduce fibrinogen levels Increase fibrinogen and fibrin degradation products Antiplatelet activators
What adverse events are associated with acetazolamide?
Metabolic acidosis (due to chronic excretion of HCO3-) Hypokalemia (acute effect) Calcium phosphate stones (due to high pH in tubule) Drowsiness, paresthesias and hypersensitivity
What molecules increase the production of angiotensinogen?
Corticosteroids Estrogens Thyroid Hormones Angiotensin II
List the class IC anti-arrhythmic drugs
Flecainide Propafenone
What are the kinin receptors,?
B1 and B2B1 are the main receptors that are responsible for the kinin biological effectsB2 are targeted by drugs to block bradykinin
What are the processes targeted by anti-angiotensin II drugs?
Block renin secretion/action Inhibit ACE function Block angiotensin receptors
What is LCZ696?
A combination of valsartan (ARB) and sacubitril (Neprilysin inhibitor) Valsartan blocks the AT1a receptor on cardiac and vascular smooth muscle Sacubitril causes vasodilation and reduced ECF volume via sodium excretion
Patients with what conditions should NOT be treated with beta blockers?
Asthma, COPD Diabetics: may mask tachycardia associated with hypoglycemia
High TG levels lead to an increased risk of what disease?
High TGs increase risk of pancreatitis
What is the major effect of nitrates?
Dilation of venous capacitance vessels
List the class IA anti-arrhythmic drugs
Procainamide Quinidine Disopyramide
What are the therapeutic uses of niacin?
Lower plasma cholesterol and TG Used in patients with familial combined hyperlipidemia and familial dysbetalipoproteinemia
What are the angiotensin antagonist drugs?
Saralasin Losartan Valsartan
What are the adverse effects of flecainide?
Increased mortality in patients with Vtach, MI, and ventricular ectopy
Why are quinidines rarely used?
- They have many adverse events in and out of the heart- Ganglion blocking & hypotension (worse than procainamide) - Anticholinergic effects require combo therapy with drug slowing AV conduction - Induce VFib, torade de pointes - Chronic use causes cinchonism
What are the targets for inhibiting NO?
1) L-arginine derivatives (L-NMMA, L-NAME) 2) Inhibit NOS synthesis 3) Inhibit binding of arginine to NOS 4) NO scavengers
What are the names of the orally active ACE inhibitors?
Captopril Enalapril
What are the effects of cAMP in cardiac muscle?
Inotropy, lusitropy, chronotropy, dromotropy
Which anti-hypertensive drugs are not used as first line drugs of choice?
Centrally acting agonists Alpha adrenergic blockersBeta blockersVasodilators
What is the mechanism of action of PCSK9 inhibitors?
PCSK9 inhibitors are human antibodies that are specific for the PCSK9 protein. They bind PCSK9 and prevent its interaction with LDLR. Result: increased expression of LDLR
What is the major ion transporter in the thick ascending limb?
Na+/K+/2Cl- cotransporter pumps these cations out of the lumen
What is the function of kallikrein?
Converts HMW kininogen to bradykinin, leading to vasodilation and hypotension
Which ADP receptor inhibitors are prodrugs that require liver transformation?
Ticlopidine, Clopidogrel and prasugrel
How does the relative ratio of cholesterol:TG differ between LDL and HDL?
LDL: 60% cholesterol, 25% TGHDL: 20% cholesterol, 5% TG, 35% phospholipid
What are the side effects of the thiazide diuretics?
HyponatremiaHyperglycemiaIncreased LDL/HDLHypokalemia
What are the 4 categories of NO donor drugs?
Ultra short (fastest acting) Short Intermediary Long (slowest acting)
What effect do bile acid-binding resins have on LDL, HDL and TGs?
Modest reduction of LDL No effect on HDL Small increase in TGs
What are the adverse effects of hydrochlorothiazide?
Hyponatremia, hypokalemia Dehydration Metabolic alkalosis Hyperuricemia Hyperglycemia Hyperlipidemia (LDL) Weakness, fatigue, paresthesia, hypersensitivity
Describe the steps that lead to the production of angiotensin III
Renin converts angiotensinogen to angiotensin IACE converts Angiotensin I to II (II is the active form)II is degraded into III
What is the molecular mechanism of amiodarone?
Blocks K+ and Na+ channels, Ca++ channels weakly, and beta receptors
What are the major substances reabsorbed and secreted in the proximal convoluted tubule?
Reabsorbed: NaHCO3, NaCl Secreted: organic acids and bases
Describe use-dependent/state-dependent drug action
A drug binding with high affinity to the active and inactive channel, but dissociating from the resting channelsThis in theory targets depolarized cells that are involved with tachyarrhthmias while leaving unaffected cells alone
What is phenoxybenzamine used for?
Treating HTN in patients with Pheochromocytoma
Side effects of verapamil
Constipation Bradycardia
What are the two classes of Ca channel blockers?
Dihydropyridines: nifedipine, nitrendipineNon-dihydropyradines: benzothiazepine (diltiazem) and phenylalkylamine (verapamil)
What advantages does lisinopril have over enalopril?
Easily absorbed Not metabolized, excreted unchanged by kidney
What are the side effects of beta blockers?
Bronchospasm Peripheral vasospasm Exaggerated cardiac effects: bradycardia, heart blockCNS effects: insomnia, depression, fatigue
What is a clinically important difference between Pravastatin and the rest of the statins?
Pravastatin is not metabolized by CYP450, unlike the other statins Fewer associated adverse events (decreased incidence of rhabdomyolysis)
What is the general effect of vasopressin?
Increased BP via increased renal resorption of water
What are the calcium channel blockers used for angina?
Dihydropyridines: nifedipine, nicardipine, amlodipineVerapamilDiltiazemBepridil
What are the other names of angiotensin converting enzyme (ACE)?
Peptidyle dipeptidaseKininase II
What are the treatment objectives for chronic CHF?
Early recognition of ventricular dysfunction Prevent ventricular remodeling Decrease symptoms: decrease congestion, increase CO Prolong survival
What drugs interact with K+ sparing diuretics?
ACE inhibitors NSAIDs
Describe the mechanism of renal disease causing systemic edema
2 Pathways:1) Urinary loss of albumin decreases plasma oncotic pressure2) reduced GFR leads to renal Na retention, water retention
What class of drugs may interact with CCBs?
Beta blockersUse together with caution
How does the action potential from a cardiac pacemaker cell differ from a ventricular cell?
Pacemaker cells do not have rapid depolarization caused by fast sodium channelsPacemaker cells also have spontaneous phase 4 depolarization unlike the ventricles
What is Niseritide and what is it used for clinically?
Niseritide is a recombinant form of BNP Used to treat CHF by inducing vasodilation and natriuresis
Describe the drug interaction between gemfibrozil and statins
Gemfibrozil inhibits OATP2 transporter, which decreases statin uptake by the liver. This leads to increased statin concentration in the blood and increased risk of myopathy, rhabdomyolysis Also inhibits glucoronidation leading to increased systemic levels of statin
What are the endothelin receptors?
ET-A and ET-B
What is the mechanism of action for spironolactone?
Competitive inhibition of aldosterone receptor -Also anti-androgenic, decreases testosterone synthesis
What fragments are formed by plasmin degradation of stabilized fibrin?
Fragments X, Y, D and E These products form D-dimers, hallmarks of DVT and DIC
Location of action of thiazides
Distal convoluted tubule
What are the anti-Xa drugs?
Apixaban Edoxaban Rivaroxaban
What are the nonpharmacological treatments for chronic CHF?
Surgical therapy Left ventricular assist devices Biventricular pacing Cardiac transplantation
What factors increase the risk for arrhythmia?
Digitalis treatment General anesthesia Acute MI
What is the treatment of warfarin overdose?
-Replacement of factors II, VII, IX, X via whole fresh blood infusion of frozen plasma -Recombinant factor VIIa -Vitamin K
What are the side effects of digitalis?
VERY NARROW THERAPEUTIC WINDOW Causes DADs and abnormal automaticity, arrhythmias
From where in the AP do EAD’s originate? How are DAD’s different?
EAD’s originate from the plateau phase, more often in slow heart ratesDAD’s originate from the resting potential, more often in high heart rates
What is the major difference between metoprolol and atenolol?
Metoprolol crosses the BBB, atenolol does not
What are the side effects of the loop diuretics?
Dehydration/hyponatremia Hypokalemia Impaired diabetes control Increased LDL/HDL Ototoxicity
What are the indications for procainamide?
Atrial and ventricular arrhythmias (rarely used today)Drug of second or third choice for post-MI ventricular arrhythmias (lidocaine, amiodarone are preferred)
What complications are associated with thrombolytic therapy?
Bleeding, re-occlusion, stroke
What are the side effects of the lipophilic beta blockers?
Insomnia Chronic fatigue
Location of action of ADH antagonists
Collecting ducts
Describe the size of heparin
Heterogenous Molecular weight varies between 2kDa and 40kDa
Increased LDL is associated with what disease?
Increased LDL is associated with an increased risk of cardiovascular disease
What are the classes of anti-arrhythmic drugs?
I: Na+ channel blockers II: beta blockers III: Prolong action potential duration IV: Ca++ channel blockers Other
How are HDL levels associated with TG levels?
Elevated TGs are associated with decreased HDL (good cholesterol)
What is the mechanism for bile acid resins increasing TG levels?
bile acids normally suppress endogenous TG synthesis, so the resins decrease bile acid levels leading to increased TG synthesis
Describe the states of the Na+ channels in cardiomyocytes
3 states, differing based on the conformation of the m (activation) and h (inactivation) gates. Resting: m closed, h open Activated: m and h open, only occurs for 1-2msec Inactivated: m open, h closedThe channels are restored from inactivated to resting state with time and/or voltage
What CCBs shouldnt be used to treat chronic hypertension?
Short acting CCBs put chronic HTN patients at high risk for MI
Which CCB has the strongest vasodilatory effect?
Nifedipine
Describe the ionic movements in the intercalated cells of the collecting tubule
H+ secreted into tubular lumen by proton pumpHCO3- reabsorbed into circulation by HCO3-/Cl- countertransport on basolateral membrane
When are vasodilators used for?
Used in combo for patients not responding to first line treatment for HTN
How does the handling of LDL change in hypercholesterolemia?
LDL levels are too high in hypercholesterolemia The LDLR-lysosome degradation of LDL cannot keep up with the high LDL levelsLDL is no longer targeted to peripheral cells, which can lead to the development of atherosclerosis
What pharmacokinetic parameter makes amiodarone treatment complicated?
Complex half life, takes very long to clear because it accumulates in several organs
What is the mechanism of action for ACE inhibitors preventing ventricular remodelling?
1) Ang II is a cardiomyocyte growth factor and fibroblast mitogen 2) Inhibit RAA system 3) Decreased wall stress
Describe where heparin is found naturally within the body
Found in mast cell granules with histamine and serotonin
What are the ACE inhibitor drugs?
Captopril Enalapril Lisinopril
What is the indication for lidocaine?
Post-MI arrhythmias Ventricular tachycardia and fibrillation after cardioversion with ischemia/infarction **Selectively inhibits conduction in depolarized cells
Which NOS isoforms are inducible, which are constitutively active?
NOS-2 is inducible NOS-1, NOS-3 are constitutive
How is kallikrein related to the coagulation cascade?
Plasma prekallikrein is also known as Fletcher factor, which promotes the intrinsic pathway of coagulation. Factor XIIa also increases kallikrein production
What is adenosine used for?
Conversion of paroxysmal supraventricular tachycardia to sinus rhythm
What is the major contraindication for losartan treatment?
Pregnancy Causes fetal renal failure
Is antiplatelet monotherapy typically used?
No, dual antiplatelet therapy is often used because single target therapy is not sufficient.
Describe the structure and function of the juxtaglomerular apparatus
Cells from distal convoluted tubule and glomerular afferent arteriole containing osmoreceptors (macula densa) and mechanoreceptors (JG cells) that regulate the RAA system via renin release
What is the mechanism of action of dipyridamole and cilostazol?
Phosphodiesterase inhibitors
Location of action of mannitol
Proximal convoluted tubule
What are the most used beta blockers for exertional angina?
Cardioselective: atenolol and metoprolol
How is warfarin metabolized?
Liver: hydroxylated in hepatic ER into inactive compound
What are the anatomical input(s) and output(s) to the kidney?
Input: renal artery Outputs: renal vein and ureter
What is the main oral anticoagulant prescribed in the US?
Warfarin
What are the indications for amiodarone?
Oral:Recurrent ventricular tachycardia or fibrillation Atrial fibrillation IV: cardiac arrest, termination of Vtach, fibrillation
What are the inhibitors of plasmin?
Aminocaproic acid, PAI-1, TAFI, alpha2 antiplasmin, alpha2 macroglobulin
What are the main pharmacological mechanisms for anti-arrhythmic drugs?
Na+ channel blockadeBlockade of sympathetic autonomic effectsProlong the effective refractory periodCa++ channel blockade
What are the most widely used NO donor drugs?
Nitrates Denitrated to release NO, cause smooth muscle relaxation
What are the beneficial effects of NO?
Smooth muscle relaxation Vasodilation Immune regulation Anesthetic effects Anti-atherosclerotic responses
How many amino acids are found in angiotensinogen, angiotensin I, and angiotensin II?
Angiotensinogen: 14 Angiotensin I: 10 Angiotensin II: 8
How does triamterene differ from amiloride?
10x less potent than amiloride with a much shorter half life
What is the general mechanism of anti-platelet drugs?
Inhibition of primary hemostatic plug formation, aggregation, activation and release mechanisms
What is ivabradine?
Funny current inhibitor Newest anti-anginal drug
What is the pathway that NO acts on?
NO interacts with the guanyl cyclase which converts GTP to cGMPThis leads to vasodilation
What are the indications for acetazolamide treatment?
Diuretic therapy (used in combination) Glaucoma (reduce intraocular pressure) Urinary alkalinization (treat overdose, stones) Acute mountain sickness
List the components of the nephron in order that filtered fluid traverses the nephron
Glomerulus Proximal convoluted tubule Loop of henle (thin descending and ascending, thick ascending) Distal convoluted tubule Collecting ducts
How do fibrates affect levels of TG, LDL, HDL?
Large reduction in TG Mild reduction in LDL Mild increase in HDL
What is the effect of ACE inhibitors on bradykinin levels?
Bradykinin levels are increased by ACE inhibitors due the inhibition of kininase II Leads to hypotension
What are the sympatholytic drugs used to treat hypertension?
Clonidine and Guanfacine Methyldopa *Both are alpha 2 agonists
What are the pathological effects of NO?
Production of free radicals Nitrosation Irritant effects
What is the mechanism of action of monteleukast and zafirleukast?
Leukotriene receptor inhibitors
What diuretics are used to treat acute CHF?
FurosemideThiazides
What class of anti-hypertensive is the best choice for uncomplicated hypertension therapy?
Diuretics
What are the side effects of clonidine?
Sedation Dry mouth Dermatitis Rebound hypertension
What is the mechanism of action of warfarin?
Inhibit II, VII, IX, X by preventing carboxylation of glutamic acid, thus preventing Ca2+ binding
How does the kidney control ECF volume?
Adjusting NaCl and H2O excretion by altering nephron permeability, regulating ion channels
Which diuretic drugs most profoundly increase urinary NaCl?
Loop agents + thiazides comboLoop agent monotherapy
Describe the pharmacokinetics of heparin
PK of heparin is dose dependent Higher doses, longer half life
What is the function of lipoprotein lipase?
Cleaves off free fatty acids from triglycerides of lipoproteins
Describe the pharmacokinetics of acetazolamide
Good oral absorption Effect begins ~30 minutes, lasts 12 hours Renal secretion via OAT
What is the mechanism of action of ezetimibe?
Inhibits NPC1L1 (protein for uptake of dietary and biliary cholesterol in small intestine) Reduces VLDL and LDL production and increases LDLR
CCBs should not be given to patients with what condition?
Contraindicated for patients with conduction disturbances, heart failure
How are beta blockers beneficial for treating arrhythmias?
Heart rate is reduced, thus decreasing intracellular Ca overload, pacemaker currents are slowed
What drugs are used to counteract the effects of thrombolytic agents?
Epsilon amino caproic acid (EACA)Tranexemic acidAprotonin
Is the thin descending limb H2O permeable or impermeable?
Permeable Water is reabsorbed from the lumen leading to concentration of the tubular fluid
What are the contraindications for thiazides?
Hypokalemia
How does warfarin cause necrosis?
Impaired functionality of protein C due to inhibition of gamma carboxylation of glutamic acid
Location of action of furosemide
Thick ascending limb
What is the antagonist of heparin?
Protamine: very basic protein derived from fish sperm Combines with heparin to form stable salt with no anticoagulant activity 1:1 antagonism
Describe the general mechanism of action of vasoactive peptides?
Act on cell surface receptors (GPCRs) leading to production of second messengers or opening of ion channels
What is the general goal of anti-arrhythmic therapy?
Reduce ectopic pacemaker activity and/or modify conduction characteristics to disable re-entry circuits
How are beta blockers useful for chronic CHF treatment?
Increased survival due to reduced LV deterioration Mechanism: reduced HR and blocking deleterious effects of chronic sympathetic stimulation
What are the drugs that inhibit GPIIb/IIIa receptors?
Tirofiban Eptifibatide Abciximab
What amino acid is digested to produce endogenous NO?
arginine
What are the clinical indications of mannitol?
-Maintenance/Increase of urine volume (Renal failure, drug overdose) -Reduce intracranial/intraocular pressure (doesn’t cross BBB or enter eye, so it pulls fluid out)
What are the drug therapies for exertional angina?
Nitrates CCBs Beta blockers Ranolazine Ivabradine
Describe the pathway for Na+ and HCO3- absorption in the proximal convoluted tubule
Transporters: Na/H antiport on lumenal side, Na/HCO3- on basolateral side 1) Na enters cells via antiporter down gradient and is pumped out via Na/K pump 2) HCO3- is converted to CO2 and H2O in the tubules by CA, which then can diffuse into the cell 3) CO2 and H2O combine to form H+ and HCO3- via intracellular CA 4) HCO3- pumped out of cell into blood
How does eplerenone differ from spironolactone?
Same MOA, but does not inhibit testosterone binding, so it has decreased side effects Much more expensive
What can alter the rate of phase 4 depolarization in cardiac pacemaker cells?
Hypokalemia, beta stimulation, and acidosis increase the rate of depolarization, thus reaching threshold fasterBeta blockade, vagal stimulation decrease the depolarization thus reaching the threshold slower
What do all arrhythmias result from?
1) disturbed impulse formation 2) disturbed impulse conduction 3) a combination of both
Side effects of nifedipine
Acute tachycardia Peripheral edema
What is the effect of neurotensin?
Vasodilation, hypotension, increased vascular permeability, hyperglycemia and inhibition of gastric motility
How is INR calculated?
INR is a normalized PT value INR = PT_patient / PT_normalcontrol
What was the original parent compound for diuretic drugs?
Sulfanilamide (an antibiotic) that causes metabolic acidosis and alkaline urine (NaHCO3 diuresis)
What effect does ezetimibe have on TG levels?
Ezetimibe does not raise TG levels (unlike bile acid resins)
What are the side effects of the non-selective beta blockers?
Increased airway resistance
How do calcium channel blockers affect the action potential?
Slower AP upstroke, slowed conduction velocityInhibition of Ca influx during AP and also during diastole
Describe the ionic movements in the principal cell of the collecting tubule
Na and water reabsorbed with ADH presentK secreted via K+ channels Basolateral Na/K ATPase Aldosterone regulates Na/K ATPase and channel expression
What is the mechanism of action of amiloride and triamterene?
Blocks Na+ channels in the principal cells, thus decreasing the driving force for K+ efflux K+ sparing
Which diuretic drugs most profoundly increase urinary NaHCO3- ?
Carbonic anhydrase inhibitors
How does membrane potential alter the availability of sodium channels?
Fewer channels are available at higher potentialsChannels close between -55 and -75 mV
What side effects are associated with reserpine?
Depression/suicidal ideationsNasal congestion
What is the definition of a diuretic?
a substance/drug that increases the discharge of urine
What is the effect of neuropeptide Y?
Vasoconstriction, mediates hypertensive responses
What are the anatomic sites of blood pressure control?
1) Arterioles 2) Veinous capacitance 3) Heart 4) Kidneys: RAA system
Why are diuretics useful for acute CHF?
Reduced preload and pulmonary venous pressureIncreases oxygenation
What primarily drives Na+ reabsorption throughout the tubule epithelial cells?
The Na/K ATPase pump on the basolateral membrane keeps a low [Na+] and a high [K+] inside the cells
What vascular beds are affected by bradykinin?
Heart, liver, kidney, intestine, skeletal muscles, liver
What is the primary determinant of the refractory period?
Action potential duration
What is the main side effect of the eicosanoids?
Hypotension
Location of action of K+ sparing diuretics
Collecting ducts
What are some causes of diuretic resistance?
NSAID useCHF or chronic renal failureNephrotic syndromeHepatic cirrhosis *Overcome via increased dose, decreased interval, add another drug
What is the mechanism of action for reserpine?
Blocks VMAT, preventing NE concentration in vesicles
What is Lp(a) and how are Lp(a) levels related to risk of atherosclerosis?
Lp(a) is a lipoprotein that prevents thrombolysis (competitive inhibition of thrombolysis pathway) Decreased levels are associated with decreased risk for atherosclerosis
Should anti-arrhythmic drugs be used in patients with asymptomatic or minimally symptomatic arrhythmias?
No. Increased mortality is associated with anti-arrhythmia treatment
How does time affect success of thrombolytic therapy?
Older clots are less susceptible to the lytic action of thrombolytic agents
What drugs prevent ventricular remodeling?
ACE inhibitors, ARB’s, LCZ696 Beta blockers Aldosterone antagonists (spironolactone)
Which angiotensin is most pharmacologically and pathologically active?
Angiotensin I
What are the potassium sparing diuretics?
Aldosterone receptor blocker: Spironolactone, Eplerenone ENaC blocker: Triamterene, Amiloride
In what situations should K+ sparing diuretics be avoided?
Hyperkalemia Patients on drugs (ACEi’s) or with diseases (DM, renal insufficiency) that could cause hyperkalemia
What is the effect of vasopeptide inhibitors (omapatrilat, sampatrilat, fasidotrilat)?
Enhanced vasodilation, reduced vasoconstriction and increased sodium excretion Mechanism: increased levels of natriuretic peptides and decreased formation of Ang II
What are the main drug-drug mechanisms leading to inhibition of warfarin’s effect?
Decreasing absorption of warfarin Increasing metabolism of warfarin
How does edema form?
If filtration exceeds lymphatic drainage, edema formsUnbalanced starling forces
What are the main drug-drug mechanisms leading to potentiation of warfarin’s effect?
Causing vit K deficiency (ABX) Displacing warfarin from albumin Decreasing clotting factor synthesis Decreasing metabolism Antiplatelet aggregating properties
Is warfarin safe to give to pregnant women?
No. Warfarin passes the placental barrier and can cause fetal malformation
Describe the drug interactions with fibrates
Strong protein binders, can displace other albumin bound drugs leading to increased concentrations of other drugs in unbound, active form Major rxn between gemfibrozil and statins (fenofibrate does not affect statin levels)
Elevated triglycerides are an independent risk factor for what diseases?
Atherosclerosis Cardiovascular disease Pancreatitis (at very high TG levels >500mg/dL)
What is the mechanism of action of hydrochlorothiazide?
Inhibition of the Na/Cl cotransporter on the lumenal side of the distal tubule
What are the symptoms of cardiac arrhythmias?
Wilde range from asymptomatic to severe hemodynamic consequences with reduced cardiac output and death
What does natriuretic mean?
Increased Na+ excretion-In addition to diuretics increasing urine output, many also increase Na+ excretion (natriuretic)
What are the indications for flecainide and propafenone?
Supraventricular arrhythmias in patients with otherwise normal hearts
What are the contraindications for acetazolamide?
Cirrhosis because serum NH3 is elevated by both liver failure and increased tubule pH
Describe the therapeutic uses of ezetimibe
Used to lower LDL in hypercholesterolemia Used in combination with statin to decrease LDL using a lower dose of statin (decrease side effects)
Describe the pharmacokinetics of furosemide
Rapid oral absorption with a short half life, short durationRenal secretion via OAT
What are the major recombinant tissue plasminogen activator drugs?
Alteplase, reteplase, and tenecteplase
Describe the structure of chemically synthesized heparin
Composed of pentasaccharide Mimics the sequence repeats found in natural heparin in order to maintain ATIII interaction
What is the mechanism of action of argatroban, bivalirudin and hirudin?
Directly inhibits IIa (thrombin)
Describe the chemical structure of heparin
Strongly acidic mucopolysaccharide with repeating units of sulfated glucuronic acid and sulfated glucosamine
What are the clinical uses of warfarin?
Prophylaxis for thrombotic disorders Treatment of established thrombus
Where are defibrinogenating agents found in nature?
Snake venom
What are the two types of calcium channel blockers and how do they differ?
Dihydropyridines: selective for smooth muscleNon-dihydropyridines: smooth muscle and cardiac pacemakers
What are the absolute contraindications of thrombolytic therapy?
Intracranial bleeding Massive hemmorhage
What channels are not present in pacemaker cells that are found in normal myocytes?
Fast sodium channels
What regulates NaCl permeability of the collecting duct?
Aldosterone
What are the 3 main categories of thrombolytic agents?
Urokinase Streptokinase Recombinant tissue plasminogen activators
What role does PCSK9 play in hypercholesterolemia?
PCSK9 is a secreted enzyme responsible for controlling the levels of LDLR expressed on liver cells. Binds to LDLR, triggers internalization and degradation of LDLR
What is the mechanism for diuretics causing hypokalemia and metabolic alkalosis?
The Na+ concentration in the lumen of the collecting duct is increased. A net negative lumenal charge drives K+ and H+ out of cells into lumen to be excreted.
Describe how diuretics reach the tubular fluid
Mannitol is filtered across the glomerulus Most others are secreted via organic acid/base transporters in the proximal tubule
Explain reverse use/state-dependence
Class III anti-arrhythmics have the least effect at fast heart rates, which is when their effects are most needed
What is the effect of substance P?
Vasodilation via release of NO
What adverse effects are associated with ADH antagonists?
hypernatremia, thirst, dry mouth, hypoteension, dizziness
What is the mechanism of action of digitalis glycosides?
Inhibit the Na/K ATPase pump which increase the Na inside the cell, this leads to increased activity of the Na/Ca exchanger, bringing more Ca into the cell and more Ca stored in the SR
What are the actions of heparin?
Plasma clearing Neutralization of vascular lining Release of tissue factor pathway inhibitor (TFPI)
Which NOS isoform is considered “bad” and is a target for drugs?
NOS-2 (the inducible isoform)
What is the treatment for moderate hypercholesterolemia?
Therapeutic lifestyle change is sufficient if there is a low cardiovascular risk
What is the general effect of endothelins?
Vasoconstriction
Side effects of ACE inhibitors
Hyperkalemia Dry cough Angioedema
Describe the clinical use of bile acid resins
Not typically used when statin therapy is an option, but are used in combination for aggressive reduciton of LDL. Statins are contraindicated in children, and women who are lactating/pregnant, so bile acid resins are a useful statin alternative
Do angiotensin receptor antagonists have any effect on the actions of ACE?
No
In what situations are adrenomodulin levels increased?
Intense exercise Hypertension Renal failure Septic shock
What role does NO play for organ transplant patients?
NO is cytoprotective, prevents cellular and platelet adhesion. Dietary arginine supplements are helpful for transplant patient management
What are the major side effects associated with NO drugs?
Hypotension
What is desmopressin?
A vasopressin analogue drugUsed for diabetes insipidus, hemophilia and vWF disease (increases VIII), and dental procedures
What is the most common electrolyte disorder in hospitalized patients? How is this treated?
Hyponatremia*Corrected with AVP receptor antagonists (vaptans)
What is the risk with aspirin resistance?
May cause recurrent ischemic vascular events in patients taking low dose aspirin
What are the main classes of antiplatelet agents?
1) Aspirin 2) COX inhibitors 3) NSAIDs 4) ADP receptor inhibitors 5) Dipyridamole 6) Cilostazol 7) GPIIb/IIIa inhibitors 8) Prostacyclin analogue
How does re-entry occur?
A unidirectional block must be presentA loop is formed from conduction down a normal branch that can loop retrograde through the block slowly and then trigger another impulse down the normal branch
What are the eicosanoids?
Monteleukast Zafirleukast Zieuton
Describe the balance between PGI2 and TXA2 and how it is modulated
Healthy individuals should COX pathways that favor PGI2 over TXA2 in order to prevent clotting. Aspirin blocks TXA2 formation in order to tip the balance in favor of PGI2
What are the major pharmacologic actions of nitric oxide?
Smooth muscle relaxation Decreased cell adhesionInflammatory response
What are the indications for ADH antagonists?
SIADHeuvolemic or hypervolemic hyponatremiaCHF
What are the new drugs developed for the treatment of homozygous familial hypercholesterolemia?
Lomitapide and Mipomersen
What is the effect of NO on ischemic and reperfusion injury?
NO has been shown to protect against ischemic and reperfusion injury
What is the effect of statins on concentrations of LDL, HDL, and TGs?
Significant reduction of LDL Modest increase in HDL Modest decrease in TGs
What effect does niacin have on TGs, LDLs and HDLs?
Reduce TGs moderately reduce LDLs moderately increase HDLs (most effective drug to raise HDL)
What are the most commonly used nitrates for angina?
NitroglycerinIsosorbide mono/dinitrate
Why is it beneficial to prolong Na+ channel recovery time for arrhythmia treatment?
Prolonging recovery time may prevent re-entry, block tachycardia and prevent premature beats from occurring by decreasing the likelihood that a new action potential will fire
What happens if NaCl intake > output?
Edema developsThis happens in heart failure, renal failure
Describe the endogenous pathway of lipoprotein metabolism
VLDL –> IDL –> LDLLDL delivers cholesterol to the periphery or back to the liver
Describe the NO treatment for pulmonary hypertension
Inhaled to improve cardiopulmonary function Essentially a low dose of viagra (INOmax)
Describe the effect of class I anti-arrhythmic drugs
Reduced conduction velocity by blocking fast sodium channels, reduces the rate and magnitude of phase 0 depolarization
What antiplatelet drugs are used to treat asthma?
Zafirleukast and ZieutonTreatment for “aZZma”
What are the first line drugs of choice for treating hypertension?
Diuretics Calcium channel blockers ACE inhibitors Angiotensin receptor blockers
What are the main protective roles of HDL against atherosclerosis?
1) Antioxidant activity: PON1 enzyme 2) Inhibit endothelial adhesion molecules 3) Prevent formation of foam cells 4) Promote reverse cholesterol transport
What are the nonpharmacological treatments of angina pectoris?
Exercise training Angioplasty Atherectomy Stents Intra-aortic balloon counterpulsation CABG
What are the major calcium channel blockers and which class do they fall in?
Nifedipine: dihydropyridine Diltiazem: nondihydropyridineVerapamil: nondihydropyridine
What are the adverse effects associated with bile acid resins?
Very few side effects because they are not absorbed or metabolized (remain in GI tract)- GI disturbances- Impaired absorption of fat soluble vitamins
How does the bioavailability of LMW heparin differ from native heparin?
LMW heparin has 100% bioavailability unlike native heparin which has ~30% bioavailability
What is the indication for ancrod?
fibrinolytic agent used to treat strokes
What adverse effects are associated with verapamil?
Vasodilation and negative inotropy can cause hypotension, fibrillation in patients with Vtach-AV block-Heart block-Constipation, nervousness, peripheral edema
What is hirudin?
A thrombin inhibitor derived from leaches Used for anticoagulation in thrombocytopenic patients
What ion is reabsorbed in the distal convoluted tubule and what regulates this reabsorption?
Ca2+ is reabsorbed in the DCT in the presence of PTH
Side effects of hyralazine
Tachycardia Angina aggrevation Fluid retention NSAIDs can reduce effectiveness
What are the systemic effects of digitalis glycosides?
Increased COIncreased renal perfusion Decreased sympathetic tone
What is the mechanism of action of Prazosin?
Selective alpha 1 antagonist
What site do anti-platelet have activity in that anticoagulants do not?
The arterial circulation
What adverse events are associated with spironolactone?
Hyperkalemia (K+ sparing) Metabolic acidosis (H+ sparing) Gynecomastia, amenorrhea, impotence, decreased libido GI upset, ulcers CNS: headache, confusion, fatigue
What type of lipid is considered “bad” cholesterol? What about “good” cholesterol?
LDL is bad cholesterolHDL is good cholesterol
Compare the potency of angiotensin II and norepinephrine
Angiotensin II is 40x more potent than NE
Are nitrates used prophylactically?
Yes. They can be used as treatment or prophylaxis for exertional angina.
What affect does spironolactone have on potassium levels and pH?
Sparing of K+ and H+ due to aldosterone inhibition -The negative lumenal charge is prevented because Na remains in lumen
What are the clinical uses of calcium channel blockers?
Angina PectorisHypertensionArrhythmiasHypertrophic cardiopyopathyMigraineRaynaud’s phenomenon
What is the relationship between ammonia excretion and urine pH?
Inversely related Increased urine pH (like due to acetazolamide treatments) will decrease ammonia excretion, thus increasing serum ammonia
What is the typical selective beta 1 blocker?
Esmolol
Describe the pharmacokinetics of hydrochlorothiazide
Good oral absorption, renal elimination Short half life (2.5 h)
What are the contraindications for beta blockers?
Acute CHF Bradycardia, heart block Peripheral vascular disease Insulin-dependent diabetes mellitus Sexual impotence Bronchospasm
What are the PCSK9 inhibitor drug names?
Alirocumab Evolocumab
What are contraindications for potassium sparing diuretic treatment?
RAS inhibitors
What is the general effect of the kinins?
Vasodilation, hypotension
What adverse effects are associated with furosemide?
Hyponatremia, kypokalemia, hypomagnesemia Dehydration Metabolic alkalosis Mild hyperglycemia
How do baseline LDL levels affect the effectiveness of statins?
Statins are effective at reducing CHD risk irrespective of the initial baseline LDL. They are the drug of choice for primary and secondary CHD prevention
Do the new oral anticoagulants require coagulation monitoring?
No.
What are the “good combinations” of drugs used to treat hypertension?
Thiazide/Loop diuretic + K+ sparing diuretic Thiazide with beta blockersCCBs with ACEi’s
What is reverse cholesterol transport?
Transport of cholesterol from periphery back to the liver where it can be secreted as bile
What are the “bad combinations” of drugs used to treat hypertension?
ACEi’s with K+ sparing diuretics ACEi’s with ARBs have no advantage in diabetics
What is the target of Dabigatran?
Factor IIa (thrombin)
What are the side effects of heparin?
Hemorrhagic complications Heparin induced thrombocytopenia Osteoporosis –> fracture risk Alopecia (loss of hair)
What are the diuretics empirically derived from sulfanilamide and how do they work?
Acetazolamide (CA inhibitor) Dichlorphenamide (CA inhibitor) Disulfamoylchloraniline (most commonly used diuretic today)
What are the most widely used ADP receptor inhibitors?
Clopidogrel and prasugrel
