Cardiovascular Pharmacology

• 1. Essential HTN
• 2. CHF
• 3. DM

• -Diuretics
• -ACEIs
• -ARBs
• -CCBs

• -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

• -ACEIs/ARBs
• -CCB
• -Diuretics
• -β-Blockers
• -α-Blockers

ACEIs: protective against diabetic nephropathy

• 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

• 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

• Commonly used drugs:
• -Nitroprusside
• -Nicardipine
• -Clevdipine
• -Labetolol
• -Fenoldopam

• Mechanism:
• -short acting
• -increase cGMP via direct release of NO

• Clinical Use:
• -Malignant hypertension

• Toxicity:
• -can cause cyanide toxicity (releases cyanide)

• Mechanism:
• -dopamine D1 receptor agonist
• -causes coronary, peripheral, renal and splanchnic vasodilation
• -decreases BP and increases natriuresis

• 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

• Goal:
• -reduction of MVO2 by decreasing 1 or more of the determinants: EDV, BP, HR, contractility, ejection time

• Nitrates
• -affect preload

• 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

• ↓ End-diastolic volume
• ↓ BP
• ↑ Contractility (reflex response)
• ↑ Heart Rate (reflex response)
• ↓ Ejection time
• ↓ MVO2

• ↑ End-diastolic volume
• ↓ BP
• ↓ Contractility
• ↓ Heart Rate
• ↑ Ejection Time
• ↓ MVO2

• No effect or ↓ End-diastolic volume
• ↓ Blood Pressure
• Little/No effect on Contractility
• ↓ Heart Rate
• Little/no Effect on Ejection Time
• ↓↓ MVO2

• 1. HMG-CoA Reductase Inhibitors
• 2. Niacin (B3)
• 3. Bile Acid Resins
• 4. Cholesterol Absorption Blockers
• 5. Fibrates

• 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

• 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)

• 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

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

• 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

Digoxin

• Pharm:
• -75% bioavailability
• -20-40% protein bound
• -T_1/2 = 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⁺

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

• 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)

• 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

• Flecainide
• Propafenone

• 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"

• Metoprolol
• Propanolol
• Esmolol
• Atenolol
• Timolol

• 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

• Amiodarone
• Ibutilide
• Dofetilide
• Sotalol

"AIDS"

• 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

• Verapamil
• Diltiazem

• Verapamil
• Diltiazem

• 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)

• Adenosine
• Mg²⁺

• Mechanism:
• -increase K⁺ out of cells → hyperpolarizing cell and decrease I_Ca
• -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

• Effective in:
• -Torsades de pointes
• -digoxin toxicity