Pharm Unit 4 Flashcards
1
Q
Heparin is found in _____ along with histamine and serotonin
A
Mast cells
2
Q
Is heparin acidic or basic?
A
Strongly acidic!
3
Q
What is the function of the heparin pentasaccharide sequence?
A
Allows heparin to bind to ATIII (co-factor)
4
Q
How many units of heparin are in a 1 mg dose?
A
120 USP units; 1 unit = 12 micrograms
5
Q
What are the actions of heparin?
A
Inhibits actions of Factor IIa and Factor Xa Also inhibits other serine proteases (IVa, XIa, XIIa) Inhibits platelet aggregation at high concentrations Causes release of tissue factor pathway inhibitor
6
Q
Heparin MOA
A
Binds to ATIII - induces conformational change in ATIII - 1000x greater affinity for clotting factors Acts as an anticoagulant
7
Q
Actions of heparin
A
Plasma clearing effect - plasma cleared of fat chylomicrons by release of lipase from vessels Causes release of tissue factor pathway inhibitor (TFPI)
8
Q
How is heparin administered?
A
IV or subcutaneous injection
9
Q
Therapeutic range for heparin is achieved when the APTT is ___x baseline
A
2-2.5x baseline value
10
Q
Endogenous modulator of heparin action
A
ATIII - heparin co-factor TFPI - released from endothelial cells Platelet factor 4 - released by activated platelets; binds to heparin and neutralizes it
11
Q
Heparin side effects
A
Hemorrhagic complications - adrenal, gut Heparin induced thrombocytopenia - patient develops antibody to heparin-platelet factor 4 complex; activation of platelets leads to thrombus formation Osteoporotic manifestations Alopecia after long term use
12
Q
Clinical uses of heparin
A
Therapeutic anticoagulation Surgical anticoagulation - only drug used for coronary bypass Prophylactic anticoagulation Thrombotic and ischemic stroke
13
Q
What compound neutralizes heparin?
A
Protamine sulfate
14
Q
Protamine is acidic or basic?
A
Strongly basic - combines with strongly acidic heparin to form a stable salt Need to give protamine as slow infusion - may cause bradycardia and hypotension
15
Q
Benefits of LMW heparin
A
Increased bioavailability (100% vs 30%) and longer course of action; only need to give one injection per day
16
Q
Example of LMW heparin
A
Enoxaparin
17
Q
Indications for antithrombin concentrates
A
Treating patients with acquired or congenital antithrombin deficiency Also useful in sepsis and DIC
18
Q
R-hirudin
A
Used in the treatment of heparin induced thrombocytopenia
19
Q
Argatroban
A
Synthetic antithrombin agent used in patient who cannot be treated with heparin; special usage in heparin induced thrombocytopenia
20
Q
Bivalirudin
A
Synthetic antithrombin agent; used for PTCA anticoagulation
21
Q
What is warfarin used for?
A
Prophylactically used to prevent thrombotic disorders and to treat established thrombi
22
Q
Warfarin MOA
A
Vitamin K analogue Warfarin inhibits Factors II, VII, IX, and X; inhibits carboxylation of glutamic acid and formation of gamma carboxyl glutamic acid (blocks vitamin K epoxide reductase)
23
Q
What test is used to measure effects of warfarin?
A
PT/INR As level of clotting factors decrease, INR value increases Therapeutic effect achieved at 1.5x baseline value
24
Q
Warfarin pharmacokinetics
A
Given orally - 100% bioavailability T 1/2 - 36 hours Highly protein bound - drugs with high binding may displace warfarin and lead to bleeding Undergoes hepatic metabolism
25
Factors that affect dose of oral anticoagulants
Nutrition - foods that contain vitamin K Anemia - high plasma volume, drug will be more diluted Liver disease - decreased coagulation proteins means greater effects of warfarin Biliary obstruction - decreased absorption of warfarin Drug interactions - especially highly protein bound drugs
26
Warfarin toxicity
Hypoprothrombinemia - echymosis, purpura, hematuria, hemorrhage All oral anticoagulants pass placental barrier and may cause fetal malformation Necrosis - due to impaired functionality of protein C
27
Treatment of warfarin toxicity
Replacement of 4 factors Recombinant Factor VIIa Vitamin K and related agents (used to treat warfarin induced hypoprothrombinemia)
28
Vitamin K and related agents
Uses: Drug induced hypoprothombinemia; intestinal disorders and surgery; hypoprothrombinemia of newborns
29
What are the oral anti-Xa agents?
Rivaroxaban Edoxaban Apixiban
30
What are the oral anti-thrombin agents?
Dabigatran
31
Rivaroxaban
Anti-Xa agent Fixed once daily dosing - good for elderly patients Renal clearance - adjust for patients with RI Potent CYP 3A4 inhibitor
32
Apixiban
Anti-Xa agent Used more often than rivaroxaban due to less renal clearance Potent CYP 3A4 inhibitor
33
Dabigatran
Anti-IIa agent Renal clearance - adjust for patient in RI Interferes with protein pump
34
Edoxaban
Half-life is 10-14 hours Decreased plasma protein binding 35% excreted by kidney 62% bioavailability
35
Light granules release:
Fibrinogen Factors V and VIII Platelet factor 4 - neutralizes heparin PDGF
36
Dark granules release:
Calcium Serotonin Histamine ADP/ATP
37
ADP receptor inhibitors (anti-platelet drugs)
Ticlopidine Clopidogrel Prasugrel Ticagrelor\* Cangrelor\* \*\* denotes drug that is already converted; the rest are prodrugs - better for patients with hepatic insufficiency
38
Dipyridamole
MOA - increases cAMP in platelets, prevents platelets from being used in thrombotic transformation Phosphodiesterase inhibitor and coronary vasodilator
39
Cilostazol
Phosphodiesterase inhibitor - anti-platelet agent Used for management of intermittent claudication
40
Abciximab
Gp IIb/IIIa inhibitor - prevents platelet aggregation Most commonly used IV agent in coronary and neurologic indications
41
Aspirin and NSAIDs
COX-1 and COX-2 inhibitors Prevent conversion of arachidonic acid to thromboxane - decrease platelet aggregation
42
Clopidogrel
ADP receptor inhibitor Prevents platelet activation Polymorphisms exist that make individuals less sensitive to clopidogrel - NOT SEEN WITH PRASUGREL
43
Antiplatelet drugs - clinical uses
Cerebrovascular disease - transient ischemic attack; stroke
Coronary artery disease - Acute MI; unstable angina
Peripheral vascular disease - venous thrombosis; peripheral arterial disease
Small vessel disease - membrane proliferative glomerulonephritis; thrombotic thrombocytopenic purpura
Prevention of thrombus formation on artificial surfaces
44
Zileuton
Inhibits lipoxygenase pathway - prevents conversion of arachidonic acid to leukotrienes
45
Montelkast
Leukotriene antagonist - used in treatment of asthma and seasonal allergies
46
Zarirlukast
Leukotriene antagonist - used in treatment of asthma
47
Omega-3 fatty acids
Lead to thromboxane A3 formation - not a potent vasoconstricting and platelet aggregating agent; decreases platelet aggregation
48
What compounds are capable of converting plasminogen into plasmin?
TPA Urokinase Streptokinase Factor XIIa
49
What are the physiological inhibitors of thrombolytics?
Plasminogen activator inhibitor 1 (PAI-1) TAFI Alpha 2 antiplasmin Alpha 2 macroglobulin
50
What is produced when stabilized fibrin clots are degraded by plasmin?
D dimers!
51
Factors which promote fibrinolysis
Plasminogen incorporation into thrombus Release of TPA by endothelial cells Binding of TPA to fibrin - TPA is an activator of thrombolysis; activates plasminogen
52
Factors which limit fibrinolysis
Fibrin crosslinking via Factor XIIIa Binding of alpha-2 antiplasmin to fibrin
53
Alteplase
Recombinant form of human TPA - most commonly used fibrinolytic agent
54
Reteplase
Mutant form of human TPA More fibrin specific Longer half life Comparable to tenecteplase
55
Clinical uses of thrombolytic agents
Acute MI - thrombus in coronary artery Peripheral arterial occlusion DVT Pulmonary embolism - only urokinase and streptokinase Thrombotic stroke - MCA occlusion Catheter clearance
56
Complications of thrombolytic therapy
Bleeding Re-occlusion due to free split products Stroke
57
Contraindications of thrombolytic therapy
Intracranial bleeding Massive hemorrhage
58
Pharmacological antagonists for thrombolytic agents
EACA - epsilon amino caproic acid Transexemic Acid Aprotonin
59
Ancrod
Snake venom-like drug that can digest fibrinogen
60
Statins - Clinical effects
20-60% reduction in LDL Modest reduction in triglycerides Modest increase in HDL
61
Statin MOA
Statins completely inhibit HMG-CoA reductase - inhibit endogenous cholesterol synthesis Activates SREBP - increases expression of LDL receptor at plasma membrane - leads to increased clearance of serum LDL and excretion in bile
62
Therapeutic uses of statins
Drug of choice for treating patients with increase LDL-C Drug of choice for both primary and secondary prevention of coronary heart disease
63
Statin adverse effects
Mostly mild GI disturbances Increase liver enzymes - rare Small increased risk of T2DM but benefits outweigh risks Major effects are on the muscles - 5-10% experience myalgia and myopathy Most serious side effect - rhabdomyolysis
64
Statin pharmacokinetics
Absorbed in intestine - 30-85% Lovastatin, simvastatin, atorvastatin metabolism by CYP 3A4 (grapefruit juice increased bioavailability of statins) Pravastatin - not metabolized by CYP 450 enzymes; good choice for patients with hepatic impairment or drug interactions
65
Ezetimibe
Cholesterol absorption inhibitor
MOA - Lowers LDL concentration, increased LDL receptor density
Therapeutic uses - decreases LDL in patients with primary hypercholesterolemia; further lowers LDL when used with statins
Adverse effects - generally well tolerated; flatulence; diarrhea
66
What are the bile acid binding resins used to treat hypercholesterolemia?
Cholestyramie
Colestipol
Colesevelam
67
Bile acid bindings resins
Cholestyramine, Colestipol, Colesevelam
Decrease LDL but **may cause slight increase in triglycerides**
MOA - bind bile acids and prevent their reabsorption; leads to increased bile acid synthesis and decreased cholesterol synthesis (via cholesterol -7a-hydroxylase); increased expression of LDL receptors
Therapeutics uses - combination with statins (dramatic decrease in LDL); used in patients in whom statins are contraindicated (pregnancy, liver dysfunction)
Adverse effects - **high concentrations** impair absorption of Vitamins A, D, E, K; may impair absorption of other drugs
Contraindications - **patients with high triglycerides**
68
What are the PCSK9 inhibitors indicated in the treatment of hypercholesterolemia?
Avrilocumab
Evolocumab
69
PCSK9 inhibitors
Avirlocumab, Evolocumab
MOA - binds PCSK9, prevent internalization and degradation of LDL rececptor; increases LDL receptor density on plasma membrane
Uses - familial hypercholesterolemia and patients that have not achieved goals with statins
**Avirlocumab leads to decrease in LDL even in presence of high dose statins**
70
Elevated triglycerides place someone at risk of what conditions?
Cardiovascular disease and **pancreatitis**
71
What is the most effective drug at raising HDL?
Niacin - 10-30% increase in HDL with a 50-80% decrease in triglycerides
72
Niacin
50-80% reduction in triglycerides, 10-30% increase in HDL
**Most effective drug for raising HDL**
MOA - complex; increased LDL clearance; increased HDL synthesis; decreased levels of Lp (a) - leads to increased thrombolysis and destruction of plaques
Indications - patients with elevated triglycerides and cholesterol - familial combined hyperlipidemia
Adverse Effects - **skin flushing and pruritis**; **can predispose gout; can exacerbate peptic ulcer disease**
Contraindications - gout; peptic ulcer disease; impaired liver function; T2DM
73
Fibrates
Fenofibrate, Gemfibrozil
MOA - decrease VLDL and increase HDL
Therapeutic Uses - high LDL associated with high triglycerides
Adverse effects - predisposition to gallstones; **Gemfibrozil** **inhibits statin glucuronidation and predisposes to rhabdomyolysis (increases concentration of all statin drugs)**
Drug interactions - highly protein bound, can displace other protein bound drugs; Gemfibrozil should not be used with statins
Contraindications - patients with renal dysfunction of pre-existing gallbladder disease
74
Omega 3 fatty acids
Reduce triglycerides 30-50%; minor increase in HDL; can increase LDL in some individuals
Therapeutic uses - adjunct to diet in individuals with triglycerides over 500 mg/dL
75
What are some common ACE inhibitors?
Captopril, Enalapril, Lisinopril
76
What are some common angiotensin receptor blockers?
Losartan, Valsartan
77
What is/what are the physiological effects of Desmopressin?
Desmopression - ADH analogue
Effects - increases Factor VIII and vWF in plasma; used in blood banking; used to control minor surgical bleeding
78
What drug is used to inhibit endothelin function?
Bosentan
79
What are some vasopeptide inhibitors and what do they do?
Omapatrilat, Sampatrilat, Fasidotrilat
Increase levels of natriuretic peptides and decrease formation of angiotensin II - leads to increase vasodilation and sodium excretion (decreases intravascular volume)
80
What receptor does Icatibant bind to and what does it do?
Binds to bradykinin B2 receptor - inhibits actions of bradykinin (can be used to treat hypotension)
81
What does Aprotonin do?
Aprotonin is a kallikrein inhibitor - prevents formation of bradykinin (inhibits vasodilation)
82
What are the thiazide diuretics used to treat hypertension?
Hydrochlorothiazide and chlorthalidone; diuretics are drugs of choice for treating uncomplicated hypertension
83
Hydrochlorothiazide
MOA - inhibit Na/Cl transporter on lumenal side of distal convoluted tubule Side effects - hyponatremia, hypokalemia, metabolic alkalosis, hyperglycemia, increased LDL/HDL ration Contraindications - hyperkalemia Drug interactions - NSAIDs, beta blockers
84
Furosemide
MOA - inhibits Na/K/2Cl transporter in loop of Henle Side effects - hyponatremia, metabolic alkalosis, hypokalemia, impaired diabetes control, increased LDL/HDL ratio, ototoxicity Drug interactions - NSAIDs, aminoglycosides (worsen ototoxicity)
85
What are the potassium sparing diuretics used to treat hypertension?
Spironolactone, eplerenone, triamterene, and amiloride
86
Spironolactone
MOA - aldosterone receptor antagonist (prevents insertion of Na channels in collecting duct; more sodium excreted, less potassium excreted) Side effects - hyperkalemia, gynecomastia Drug interactions - NSAIDs, ACE inhibitors and angiotensin receptor blockers (potentiate hyperkalemia) Contraindications - renin-angiotensin-aldosterone system inhibitors (potentiate hyperkalemia)
87
What are the two types of calcium channel blockers?
Dihydropyridines - block calcium channels in vascular smooth muscle Non-dihydropyridines - block calcium channels in vascular smooth muscle and cardiac muscle
88
Calcium channel blocker MOA
All reduce vascular resistance by reducing calcium influx in vascular smooth muscle Non-dihydropyrides also reduce pacemaker potential, AV node conduction, and contractility \*ND blockers contraindicated in patients with conduction disturbances, use with caution in patients on beta blockers, avoid use for chronic hypertension
89
Nifedipine
Dihydropyridine calcium channel blocker (limited effect on pacemaker or conduction/contractility) Side effects - acute tachycardia, peripheral edema
90
Diltiazem
Non-dihydropyridine calcium channel blocker Side effects - bradycardia
91
Verapamil
Non-dihydropyridine calcium channel blocker Side effects - bradycardia and constipation
92
Clonidine
MOA - alpha 2 adrenergic receptor agonist (decreases sympathetic outflow from CNS) Withdraw drug slowly to avoid rebound hypertension Side effects - sedation, dry mouth, bradycardia Guanfacine - similar, longer half life and less chance of rebound
93
Methyldopa
MOA - converted to methylnorepinephrine (alpha 2 agonist, decreases sympathetic CNS outflow); also competes with L-DOPA for dopamine carboxylase (decreases dopamine production) Interactions - Levodopa Side effects - sedation (decreased sympathetic activation)
94
Reserpine
MOA - blocks VMAT vesicular transport (prevents NE storage in vesicles) Combined with diuretics, used for patients who are resistant to many other drugs Side effects - depression, nasal congestion Drug interactions - CNS depressants, MAOIs
95
Phenoxybenzamine
MOA - non-selective alpha adrenergic receptor antagonist Side effects - tachycardia (NE binding to beta-1 receptors since alpha are blocked)
96
Prazosin
MOA - selective alpha-1 adrenergic antagonist; less tachycardia than direct vasodilators Side effects - hypotension Terazosin and doxazosin have longer half lives
97
Propranolol
MOA - non-selective beta blocker Used as adjunct to prevent tachycardia
98
Nadolol
MOA - non-selective beta blocker Longer half life than propranolol
99
Pindolol
MOA - non-selective partial agonist beta blocker Less bradycardia than other beta blockers
100
Metoprolol
MOA - selective beta-1 blocker, somewhat lipophilic (can get into brain and decrease anxiety)
101
Atenolol
MOA - selective beta-1 blocker Hydrophilic, eliminated by kidneys
102
Labetolol
MOA - beta blocker with some alpha blocking capacity Lipophilic
103
Carvedilol
MOA - non-selective beta blocker and alpha receptor antagonist Acts as a vasodilator
104
Beta blocker side effects
Bradycardia
Increased triglycerides
Hyperglycemia
Impaired exercise tolerance
Increased airway resistance (non-selectives)
Insomnia and chronic fatigue - lipophilic beta blockers
Can mask and prolong insulin-induced hypoglycemia
**Less efficacious as monotherapy in African Americans but efficacious when combined with beta blockers**
105
Hydralazine
MOA - vasodilator, used in drug resistant hypertension or emergency
Side effects - tachycardia, angina aggravation, fluid retention
NSAIDs reduce effectiveness
106
Minoxidil
MOA - vasodilator, used to treat drug resistant hypertension
107
Nitroprusside
MOA - vasodilator, used in emergencies
Side effects - cyanide poisoning
108
ACE inhibitors
MOA - block production of angiotensin II (vasoconstrictor and aldosterone releasing agent); increases circulating levels of bradykinin
Side effects - increased bradykinin may lead to dry cough, hyperkalemia, angioedema
Captopril - short half life
Enalapril - converted to active metabolite, longer half life, longer onset of action
Lisinopril - water soluble
Contraindications - pregnancy, bilateral renal stenosis
**ACE inhibitors prolong survival in patients with heart failure or left ventricular dysfunction after MI**
**Preserve renal function in diabetic patients**
109
Losartan
MOA - angiotensin receptor blocker (mediate vasoconstriction and sodium retention)
Side effects - hyperkalemia
Contraindications - pregnancy
Drug interactions - K sparing drugs
110
Good combinations of hypertensive medications
Thiazide/loop diuretic + potassium sparing diuretic
Thiazide diuretic + beta blocker
Calcium channel blocker + ACE inhibitor
111
Preferred therapy for DM
ACE inhibitors
112
Preferred therapy for heart failure
ACE inhibitors
113
Preferred therapy for MI
ACE inhibitors, beta blockers
114
Consideration for pregnancy
Avoid ACE inhibitors or ARBs
115
Considerations for AA
Monotherapy with diuretics or calcium channel blockers most efficacious; avoid monotherapy with beta blockers, ACE inhibitors
116
Considerations for elderly
Give drugs in small increments, monitor side effects closely
117
Considerations for obstructive airway disease
Avoid non-selective beta blockers
118
Procainamide
Class IA sodium channel blocker
Slows upstroke of the AP, conduction, prolongs QRS complex Indications - atrial and ventricular arrhythmia
Side effects - risk of hypotension; can induce torsades de pointes (ventricular tachycardia); long term use can lead to lupus erythematosus
119
Quinidine
Class IA sodium channel blocker
Rarely used because of cardiac and extra-cardiac adverse effects
Side effects - can induce V-fib and torsades de pointes; **cinchonism - headache, dizziness, tinnitus**
120
Lidocaine
Class IB sodium channel blocker
Selective depression of conduction in depolarized cells
**First choice for treating ventricular tachycardia and fibrillation after cardioversion in ischemia/infarct**
Metabolism - extensive first pass metabolism (increased concentration in liver disease)
Side effects - **least cardiotoxic of class I drugs**; may induce hypotension (decreased contractility); some neuro side effects due to anesthetic properties (nausea, lightheadededness, hearing disturbances)
121
Mexiletine
Class IB sodium channel blocker
Orally available lidocaine analogue
Can be used off label for chronic pain
122
Flecainide
Class IC sodium channel blocker
**Used to treat supraventricular arrhythmia in patients with otherwise normal hearts**
Increases mortality in patients with ventricular tachyarrhythmia, MI, ventricular ectopy
123
Propafenone
Class IC sodium channel blocker
Used to treat supraventricular arrhythmia in patients with otherwise normal hearts
Side effects - same effects as flecainide plus bradycardia, bronchospasm
124
Amiodarone
Class III drug - prolongs AP duration
Structural analogue of thyroid hormone
Effects - blocks K and Na channels, weakly blocks Ca channels, inhibits beta receptors; prolongs refractoriness and slows conduction
Indications - recurrent v-tach or fibrillation; atrial fibrillation; drug of choice for out of hospital cardiac arrest, termination of ventricular tachycardia or fibrillation
Adverse effects - bradycardia/heart block; pulmonary toxicity (may lead to fibrosis); blocks conversion of T4 to T3
125
Dronedarone
Similar to amiodarone but without effects on thyroxine metabolism
Contraindicated in severe or recently decompensated symptomatic heart failure
126
Verapamil
Class IV calcium channel blocker
High cardiac selectivity; directly slows AV node conduction and refractorines; slows SA node automaticity
Indications - **supraventricular arrhythmia (drug of choice)**; re-entry arrhythmia, tachycardia involving AV node; slows ventricular rate in atrial flutter/fibrillation
Side effects - negative inotropic effects; contraindication in ventricular tachycardia (can lead to hypotension); vasodilation; peripheral edema
127
Diltiazem
Class IV calcium channel blocker
Similar effects as verapamil
128
Adenosine
Acts via purinergic receptors to increase K+ conductance (leads to hyperpolarization)
Primary action on atrial tissue - slows AV node conduction and increases AV node refractoriness
**Drug of choice for converting paroxysmal SVT to sinus rhythm**
Side effects - bradycardia, sinus pauses, AV block, hypotension
129
What effect on the heart do vagal maneuvers have? (diving reflex/Valsalva maneuver)
Slow conduction through the AV node - acute treatment for paroxysmal SVT
130
What are the drugs of choice for treating uncomplicated hypertension?
Diuretics
131
Hydrochlorothiazide/Chlorthalidone
MOA - inhibit Na/Cl cotransporter in distal convoluted tubule; decrease blood volume
Side effects - hyponatremia; hypokalemia; hyperglycemia; increased LDL/HDL ratio
Contraindications - hypokalemia
Relative contraindication - pregnancy (patient can stay on if previously on it but needs to be monitored)
Can be combined with beta-blockers, ACE inhibitors, aldosterone receptor blockers, centrally acting hypertensives
Drug interactions - NSAIDs
132
Furosemide
Loop diuretic - inhibits Na/K/2 Cl transporter in thick ascending loop
Side effects - hyponatremia; hypokalemia; metabolic alkalosis; impaired diabetes control; increased LDL/HDL ratio; ototoxicity
Drugs interactions - NSAIDs; aminoglycosides (worsens ototoxicity)
133
Spironolactone
Potassium sparing diuretic
MOA - aldosterone receptor antagonist
Side effects - hyperkalemia; gynecomastia
Drugs interactions - NSAIDs; ACE inhibitors and angiotensin receptor blockers (exacerbate effects, hyperkalemia due to less aldosterone activation and less potassium excretion)
Contraindications - RAS inhibitors (can exacerbate hyperkalemia)
134
Nifedipine
Dihydropyridine calcium channel blocker (specific for vascular smooth muscle)
Side effects - acute tachycardia (baroreflex); peripheral edema (vasodilator effect)
135
Diltiazem
Non-dihydropyridine calcium channel blocker (vascular and cardiac smooth muscle)
Side effects - bradycardia
136
Verapamil
Non-dihydropyridine calcium channel blocker (vascular and cardiac smooth muscle)
Side effects - bradycardia and constipation
137
Who are non-dihydropyridines contraindicated in?
Patients with conduction disturbances; use with caution in patients who are taking beta-blockers (can cause severe bradycardia)
138
Clonidine
MOA - alpha 2 receptor agonist; decreases sympathetic outflow from CNS (acts as a vasodilator, decreased action at alpha 1 receptors)
Must withdraw drug slowly to avoid rebound hypertension
Side effects - sedation; dry mouth (sympathetic NS leads to salivation); bradycardia
Guanfacine has longer half life and less chance of rebound
139
Methyldopa
MOA - competes for DOPA decarboxylase with L-DOPA; acts as an alpha 2 agonist following metabolism
Most extensively used anti-hypertensive in pregnancy
Side effects - sedation; decreased dopamine production
Interactions - levodopa (decreases dopamine production)
140
Reserpine
MOA - blocks VMAT vesicular transport (prevents storage of NE centrally and peripherally; less NE = less alpha 1 activation = lower BP)
Combined with other diuretics - **used for patients who are resistant to other drugs**
Side effects - depression; nasal congestion
Drug interactions - CNS depressants; MAOIs (buildup of NE in the cytosol leads to inappropriate release)
141
Phenoxybenzamine
Non-selective alpha adrenergic antagonist
Side effects - tachycardia (blockade of alpha receptors causes NE to bind to beta-1 receptors)
142
Prazosin
MOA - selective alpha 1 adrenergic antagonist
Less tachycardia than direct vasodilators
Terazosin and Doxazosin have longer half lives than Prazosin
Side effects - hypotension (blockade of alpha 1 receptor); may decrease LDL/HDL ratio - good for patients with hyperlipidemia
143
Beta-blockers
MOA - decrease contractility, reduce cardiac output, decrease renin release (less vasoconstriction)
Side effects - bradycardia, hyperglycemia (can mask and prolong insulin-induced hypoglycemia), increased airway resistance in non-selectives
Drug interactions - calcium channel blockers (decreased contractility and conduction)
Contraindications - cardiogenic shock, sinus bradycardia, asthma, severe heart failure Less efficacious as monotherapy in AA, efficacious when combined with diuretic
144
When should vasodilators be indicated in hypertension?
Used for patients who are resistant to other therapies or in emergencies
145
Hydralazine
Used in drug resistant hypertension or in emergency
Side effects - tachycardia (baroreflex to low BP); angina aggravation (decreased venous return); fluid retention
146
ACE inhibitors
Captopril, Enalapril, Lisinopril
MOA - block production of angiotensin II and downstream aldosterone; increase levels of bradykinin Captopril - short half life Enalapril - longer half life, has to be converted to metabolite Lisinopril - water soluble, excreted unchanged by kidney
Side effects - hyperkalemia; dry cough (associated with bradykinin); angioedema (allergic reaction, skin and mucosal swelling)
Drug interactions - exacerbates hyperkalemia with potassium sparing diuretics
Contraindications - pregnancy (need ATII for normal development); bilateral renal stenosis
**Prolong survival in patients with HF or LV dysfunction following MI** (prevent remodeling)
Preserve renal function in diabetics
147
Losartan
MOA - angiotensin II receptor blocker (decreased vasoconstriction and sodium retention)
Selectively blocks AT1 receptor
Side effects - hyperkalemia
Contraindications - pregnancy
Drug interactions - K+ sparing diuretics
148
What is the mechanism of action of nitrates in vivo?
Decrease venous return
Decrease LV wall tension
Reduce afterload
Direct coronary artery vasodilation
149
Clinical uses of nitrates
Angina pectoris (stable, unstable, Prinzmetal)
Hypertensive crisis
Congestive heart failure (decrease venous return to heart)
150
Side effects of nitrates
Exaggeration of therapuetic effects - orthostatic hypotension; reflex tachycardia; headache
Nitrate tolerance - leads to nitrosylation of proteins
151
Clinical uses of calcium channel blockers
Angina pectoris
Hypertension
Arrhythmias (slow SA node conduction)
Hypertrophic cardiomyopathy
Migraine
152
What are the dihydropyridine calcium channel blockers and what do they do?
Nifedipine Amlodipine Nicardipine
Act on vascular smooth muscle calcium channels - lead to vasodilation
153
What are the non-dihydropyridine calcium channel blockers and what do they do?
Verapamil Diltiazem Bepridil
Act on vascular but also cardiac calcium channels - have negative inotropic and chronotropic effects (decrease HR and contractility)
154
Side effects of calcium channel blockers
Bradycardia (verapamil)
CHF (verapamil - due to decreased contractility)
Heart block
Hypotension
Reflex tachycardia
Peripheral edema
155
Clinical effects of beta blockers
Decreased HR
Decreased contractility
Decreased myocardial oxygen demand
Increased diastolic perfusion
Increased oxygen supply
156
Clinical uses of beta blockers
Angina pectoris
Hypertension
Arrhythmia
Dissecting aortic aneurysm
Mitral valve prolapse
Post MI prophylaxis (prevents remodeling)
Hyperthyroidism
Migraine
157
Nonselective beta blockers with intrinsic sympathomimietic activity
Pindolol Labetalol
158
Cardioselective beta blockers with intrinsic sympathomimetic activity
Acebutolol
159
Side effects of beta blockers
Bronchospasm
Peripheral vasospasm
Exaggeration of therapeutic effects - heart block; bradycardia
CNS effects - insomnia; depression; fatigue
160
Beta blocker contraindications
Insulin-dependent diabetes
Acute CHF
Advanced AV nodal block
Peripheral vascular disease
Bronchospasm
Marked bradycardia
Sexual impotence
161
Ivabradine
MOA - funny current inhibitor; indicated in patients who cannot take beta blockers
Side effects - luminous phenomenon; bradycardia; AV nodal block
162
What are common causes of acute CHF?
Large MI (involving over 40% ventricle)
Myocarditis
Arrhythmia
Cardiac tamponade
Pulmonary embolism
Acute valvular regurgitation
163
What are common causes of chronic CHF?
Ischemic cardiomyopathy (most common in US)
Hypertrophic cardiomyopathy (HTN, stenosis, cor pulmonale)
Dilated cardiomyopathy (regurgitation, alcohol, genetic causes, idiopathic)
164
What are the treatment objectives in acute CHF?
Reduce symptoms
Decrease pulmonary congestion (loop diuretics, venodilators)
Increase cardiac contractility (beta agonists)
Reduce afterload (nitroprusside)
165
Diuretics used in acute CHF
Furosemide (Na/K/2Cl blocker - potent diuretic, rapid onset of action)
Thiazides - weaker, can be used with loop diuretics in patients resistant to furosemide
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Side effects of diuretics
Overdiuresis
Hyponatremia
Hypokalemia
Ototoxicity
Allergies (loop and thiazides are sulfa drugs)
Diuretic resistance (overcome by using drugs in combinations)
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Niseritide
MOA - promotes natriuresis and vasodilation; used to treat acute congestive heart failure
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Beta agonists used to treat acute CHF
MOA - increase cardiac contractility (contractility depressed in many forms of CHF)
Isoproterenol Dopamine Dobutamine NE
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Beta agonists increase cAMP in cardiac myocytes. What do increased cAMP levels lead to?
Increased opening of L type calcium channels
Increase reuptake of calcium into the SR
Increased pacemaker current
Increased rate of conduction
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What class of drugs is contraindicated in acute CHF?
Calcium channel blockers - lead to decreased contractility
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What are the treatment objectives in chronic CHF?
Reduce pulmonary congestion
Reduce afterload
Increase contractility (digitalis)
Prevent ventricular remodeling
Increase survival
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What drug is used in chronic CHF to increase contractility?
Digitalis
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What is the MOA of digitalis?
Partial inhibitor of Na/K ATPase; leads to increase intracellular and SR calcium; more calcium released with each contraction
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Mechanical effects of digitalis
Increased velocity of fiber shortening and force of contraction
Increased ventricular emptying
Decreased end-systolic and end-diastolic volumes
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Systemic effects of digitalis
Increased cardiac output
Increased renal perfusion
Decreased sympathetic activity
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What are some side effects associated with digitalis use?
DADs and abnormal automaticity
VPBs
V tach
Junctional tach
Side effects treated by administering digibind antibodies
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What patient population is digitalis primarily used in?
Used in patients with CHF and atrial fibrillation with rapid ventricular response
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What is the MOA whereby ACE inhibitors prevent ventricular remodeling in CHF?
ACE inhibitors prevent formation of angiotensin II - angiotensin II is a potent cardiomyocyte growth factor and fibroblast mitogen Leads to reduced systolic and diastolic wall stress
Angiotensin II is also a potent vasoconstrictor - blockade leads to vasodilation and reduction in afterload
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Are beta blockers indicated in chronic CHF?
YES! Beta blockers increase survival and prevent deterioration of LV performance in patients with mild-moderate CHF
Prevents deleterious effects of chronic sympathetic activation
