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Antihypertensive Therapy
- 1. Essential HTN
- 2. CHF
- 3. DM
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Antihypertensive Therapy: Essential HTN
- -Diuretics
- -ACEIs
- -ARBs
- -CCBs
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Antihypertensive Therapy: CHF
- -Diuretics
- -ACEIs/ARBs
- -β-Blocker (compensated CHF)
- -K+ Sparing diuretics
**β-Blockers must be used cautiously in decompensated CHF and are CI in cardiogenic shock
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Antihypertensive Therapy: Diabetes Mellitus
- -ACEIs/ARBs
- -CCB
- -Diuretics
- -β-Blockers
- -α-Blockers
ACEIs: protective against diabetic nephropathy
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Calcium Channel Blockers
- DHP:
- -Nifedipine
- -Amlodipine
- Non-DHP:
- -Verapamil
- -Diltiazem
- Mechanism:
- -block voltage gated L-type calcium channels
- -reduces contractility
- -DHP: effect predominantly vascular smooth muscle
- -Non-DHP: effect vascular smooth muscle and cardiac muscle
- Vascular smooth muscle:
- amlodipine = nifedipine > diltiazem > verapamil
- Heart:
- verapamil > diltiazem > amlodipine = nifedipine
- "Verapamil = Ventricle"
- Clinical Use:
- -HTN-angina
- -arrhythmias (NOT nifedipine)
- -Prinzmetal's angina
- -Raynaud's
- Toxicity:
- -Cardiac depression
- -AV block
- -peripheral edema
- -flushing
- -dizziness
- -constipation
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Hydralazine
- Mechanism:
- -increase cGMP → smooth muscle relaxation
- -vasodilates arterioles > veins
- -afterload reduction
- Clinical Use:
- -severe HTN
- -CHF
- -First line for HTN in pregnancy (with methyldopa)
- -frequently given with β-blocker to prevent reflex tachycardia
- Toxicity:
- -compensatory tachycardia (CI: angina/CAD)
- -fluid retention
- -nausea
- -HA-angina
- -Lupus-like syndrome
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Malignant HTN Treatment
- Commonly used drugs:
- -Nitroprusside
- -Nicardipine
- -Clevdipine
- -Labetolol
- -Fenoldopam
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Nitroprusside
- Mechanism:
- -short acting
- -increase cGMP via direct release of NO
- Clinical Use:
- -Malignant hypertension
- Toxicity:
- -can cause cyanide toxicity (releases cyanide)
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Fenoldopam
- Mechanism:
- -dopamine D1 receptor agonist
- -causes coronary, peripheral, renal and splanchnic vasodilation
- -decreases BP and increases natriuresis
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Nitroglycerin, Isosorbide Dinitrate
- Mechanism:
- -vasodilate by releasing NO in smooth muscle
- -causing increase cGMP and smooth muscle relaxation
- -dilate veins >> arteries
- -decreases preload
- Clinical Use:
- -angina
- -pulmonary edema
- Toxicity:
- -reflex tachycardia
- -hypotension
- -flushing
- -HA
- "Monday Disease"
- -in industrial exposure
- -development of tolerance for the vasodilating action during work week and loss of tolerance over the weekend
- -results in tachycardia, dizziness, and HA upon re-exposure
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Antianginal Therapy
- Goal:
- -reduction of MVO2 by decreasing 1 or more of the determinants: EDV, BP, HR, contractility, ejection time
- β-Blockers
- -affect afterload
- Calcium Channel Blockers
- -Nifedipine is similar to Nitrates in effect
- -Verapamil is similar to β-Blockers in effect
- Pindolol and acebutolol-partial β-Blockers that are CI in angina
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Antianginal Therapy: Effects of Nitrates
- ↓ End-diastolic volume
- ↓ BP
- ↑ Contractility (reflex response)
- ↑ Heart Rate (reflex response)
- ↓ Ejection time
- ↓ MVO2
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Antianginal Therapy: Effects of β-Blockers
- ↑ End-diastolic volume
- ↓ BP
- ↓ Contractility
- ↓ Heart Rate
- ↑ Ejection Time
- ↓ MVO2
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Antianginal Therapy: Effects of Nitrates + β-Blockers
- No effect or ↓ End-diastolic volume
- ↓ Blood Pressure
- Little/No effect on Contractility
- ↓ Heart Rate
- Little/no Effect on Ejection Time
- ↓↓ MVO2
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Lipid Lowering Agents
- 1. HMG-CoA Reductase Inhibitors
- 2. Niacin (B3)
- 3. Bile Acid Resins
- 4. Cholesterol Absorption Blockers
- 5. Fibrates
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HMG-CoA Reductase Inhibitors
- Lovastatin
- Pravastatin
- Simvastatin
- Atorvastatin
- Rosuvastatin
- Mechanism:
- -inhibit conversion of HMG-CoA to mevalonate, a XOL precursor
- Effect on LDL: ↓↓↓
- Effect on HDL: ↑
- Effect on TGs: ↓
- Side Effects:
- -hepatotoxicity (increased LFTs)
- -rhabdomyolysis
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Niacin (B3)
- Mechanism:
- -inhibits lipolysis in adipose tissue
- -reduces hepatic vLDL secretion into circulation
- Effect on LDL: ↓↓
- Effect on HDL: ↑↑
- Effect on TGs: ↓
- Side Effects:
- -red, flushed face (decreased by aspirin or long term use)
- -hyperglycemia (acanthosis nigricans)
- -hyperuricemia (exacerbates gout)
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Bile Acid Resins
- Cholestyramine
- Colestipol
- Colesevelam
- Mechanism:
- -prevent intestinal reabsorption of bile acids
- -liver must use XOL to make more
- Effect on LDL: ↓↓
- Effect on HDL: slighty ↑
- Effect on TGs: slightly ↑
- Side Effects:
- -patients hate it
- -tastes bad
- -causes GI discomfort
- -decreased absorption of fat soluble vitamins
- -cholesterol gall stones
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Cholesterol Absorption Blockers
Ezetimibe
- Mechanism:
- -Prevent XOL reabsorption at small intestine brush border
- Effect on LDL: ↓↓
- Effect on HDL: --
- Effect on TGs: --
- Side Effects:
- -rare increase in LFTs
- -diarrhea
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Fibrates
- Gemfibrozil
- Clofibrate
- Bezafibrate
- Fenofibrate
- Mechanism:
- -upregulate LPL → increased TG clearance
- Effect on LDL: ↓
- Effect on HDL: ↑
- Effect on TGs: ↓↓↓
- Side Effects:
- -myositis
- -hepatotoxicity (increased LFTs)
- -XOL gallstones
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Cardiac Glycosides
Digoxin
- Pharm:
- -75% bioavailability
- -20-40% protein bound
- -T1/2 = 40 hours
- -urinary excretion
- Mechanism:
- -direct inhibition of Na+/K+ ATPase
- -leads to indirect inhibition of Na+/Ca2+ exchanger/antiport
- -decreases intracellular Ca2+ concentration → positive ionotropy
- -stimulates vagus nerve → decreased HR
- Clinical Use :
- -CHF (increase contractility)
- -A Fib (decrease conduction at AV node and depression of SA node)
- Toxicity:
- 1. Cholinergic:
- -nausea/vomiting
- -diarrhea
- -blurry yellow vision (think Van Gogh)
- 2. EKG:
- -↑ PR
- -↓ QT
- -ST scooping
- -T wave inversion
- -arrhythmia
- -AV block
- 3. Hypokalemia
- -poor prognostic indicator
- Factors Predisposing to Toxicity:
- -renal failure (decreased excretion)
- -hypokalemia (permissive for digoxin binding at K+ binding site on Na+/K+ ATPase)
- -Quinidine (decreased digoxin clearance, displaces digoxin from tissue-binding sites)
- Antidote:
- -slowly normalize K+
- -lidocaine
- -cardiac pacer
- -anti-digoxin Fab fragments
- -Mg2+
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Antiarrhythmics: Na+ Channel Blockers (Class I)
Local anesthetics
- Mechanism:
- -slow or block conduction (especially in depolarized cells)
- -decrease phase 0 slope and increased threshold for firing in abnormal pacemaker cells
Are state dependent: selectively depress tissue that is frequently depolarized (eg: tachycardia)
Hyperkalemia causes increased toxicity for all Class I drugs
- Class IA:
- -Quinidine
- -Procainamide
- -Disopyramide
- "The Queen Proclaims Diso's pyramid"
- Class IB
- -Lidocaine
- -Mexiletine
- -Tocainide
- "I'd Buy Lidy's Mexican Tacos"
- Class IC
- -Flecainide
- -Propafenone
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Class IA Antiarrhythmics
- Quinindine
- Procainamide
- Disopyramide
"The Queen Proclaims Diso's pyramid"
- Mechanism:
- -↑ AP duration
- -↑ effective refractory period (ERP)
- -↑ QT interval
- Clinical Uses:
- -affect both atrial and ventricular arrhythmias
- -especially reentrant and ectopic supraventricular and ventricular tachycardia
- Toxicity:
- -thrombocytopenia
- -torsades de pointes due to ↑ QT interval
- -Quinidine (cinchonism: HA, tinnitus)
- -Procainamide (reversible SLE-like syndrome)
- -Disopyramide (HF)
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Class IB Antiarrhythmics
- Lidocaine
- Mexiletine
- Tocainide
"I'd Buy Lidy's Mexican Tacos"
**Phenytoin can also fall into the IB category
- Mechanism:
- -↓ AP duration
- -preferentially affect ischemic or depolarized Purkinje and ventricular tissue
- Clinical Use:
- -acute ventricular arrhythmias (esp post-MI)
- -digitalis induced arrhythmias
"IB is Best post-MI"
- Toxicity:
- -local anesthetic
- -CNS stimulation/depression
- -CV depression
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Class IC Antiarrhythmics
- Mechanism:
- -no effect on AP duration
- Clinical Use:
- -Useful in ventricular tachycardias that progress to VF and in intractable SVT
- -usually used only as last resort in tachyarrhythmias
- -for patients without structural abnormalities
- Toxicity:
- -proarrhythmic, especially post-MI (Contraindicated!!!)
- -significantly prolongs the refractory period at the AV node
"IC is Contraindicated in structural heart disease and post-MI"
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Antiarrhythmics: β-Blockers (Class II)
- Metoprolol
- Propanolol
- Esmolol
- Atenolol
- Timolol
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Class II Antiarrhythmics
- Metoprolol
- Propanolol
- Esmolol
- Atenolol
- Timolol
- Mechanism:
- -decrease SA and AV node activity by decrease cAMP and decreasing Ca2+ currents
- -suppresses abnormal pacemakers by decreasing phase 4 slope
- -AV node is particularly sensitive (increased PR interval)
- *esmolol is very short acting
- Clinical Use:
- -ventricular tachycardia
- -SVT
- -slowing ventricular rate during Afib and A flutter
- Toxicity:
- -impotence
- -exacerbation of asthma
- -CV effects (bradycardia, AV block, CHF)
- -CNS effects (sedation, sleep alterations)
- -may mask signs of hypoglycemia
- -Metoprolol: may cause dyslipidemia
- -Propanolol: can exacerbate vasospasm in Prinzmetal's angina
- Overdose:
- -tx with glucagon
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Antiarrhythmics: K+ Channel blockers (Class III)
- Amiodarone
- Ibutilide
- Dofetilide
- Sotalol
"AIDS"
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Class III Antiarrhythmics
- Amiodarone
- Ibutilide
- Dofetilide
- Sotalol
"AIDS"
- Mechanism:
- -increase AP duration
- -increase ERP
- -increase QT interval
- Clinical Use:
- -when other antiarrhythmics fail
- Toxicity:
- 1. Sotalol:
- -torsades de pointes
- -excessive β block
- 2. Amiodarone:
- -pulmonary fibrosis
- -hepatotoxicity
- -hypo/hyperthyroidism (amiodarone is 40% iodine)
- -corneal deposits
- -skin deposits (blue/gray) resulting in photodermatitis
- -neurologic effects
- -constipation
- -CV effects (bradycardia, heart block, CHF)
**Amiodarone has class I, II, III and IV effects b/c it alters the lipid membrane
Remember to check PFTs, LFTs and TFTs when using amiodarone
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Antiarrhythmics: Ca2+ Channel blockers (Class IV)
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Class IV Antiarrhythmics
- Mechanism:
- -decrease conduction velocity
- -increase ERP
- -increase PR interval
- Clinical Use:
- -prevention of nodal arrhythmias (SVT)
- Toxicity:
- -constipation
- -flushing
- -edema
- -CV effects (CHF, AV block, SA depression)
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Adenosine
- Mechanism:
- -increase K+ out of cells → hyperpolarizing cell and decrease ICa
- -very short acting (~15 sec)
- Clinical Use:
- -drug of choice in diagnosing/abolishing supraventricular tachycardia
- Toxicity:
- -flushing
- -hypotension
- -chest pain
Effects blocked by theophyline and caffeine
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Mg2+
- Effective in:
- -Torsades de pointes
- -digoxin toxicity
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