Drugs

    .

    UNDER CONSTRUCTION

     

    Nitrates

    Drugs:

     

    PDE-5 Inhibitors (for erectile dysfunction, contraindicated)

       Sildenafil (~24hr clearance)

       Vardenafil (~24hr clearance)

       Tadalafil [Cealis] (TADA!! lasts 3-4 days)

    Mechanism:

    - Coronary and systemic vasodilation.

    - As effective as BB and CCB in reducing angina

    - Effectiveness depends on free period of 8-12hrs/day.

         (Tolerance quickly develops if used continuously)

    Indications:

    - Chronic stable angina

       - Recommended carry SL or Spray nitrates

    Contraindications: - Erectile dysfunction meds (Severe hypotension)


    Calcium Channel Blockers

    Drugs:

    Dihydropuridine

      Amlodipine

    Non-Dihydropuridine

      Diltiazem

      Verapamil

    Mechanism:

     

    Indications:

    - 1st line for vasospastic angina (aka Prinzmetal angina)

    - Used in combination with BB and Nitrates if angina not controlled with BB alone.

    Side Effects/Cautions:

    - CAREFUL: renal failure or dialysis, can accumulate and cause conduction disease.

    - Peripheral edema (does not rise BNP)

    - Some decrease heart rate (esp non-dihydropuridines) and can have negative 

      inotropic effects.

       Hence: DO NOT use in LV systolic dysfunction.

    Notes:

    - Patients often prefer over BB due to preserved exercise capacity

      , preserved QOL, less sexual dysfunction.

     

    CCBSummary.png

     

    Nitrates

    • Formulation Name Dose NOTES
      Sulingual  Nitro Spray 0.4mg/spray Up to 3 sprays at a time (monitor BP)
      Transdermal Nitro patch

      0.4mg/hr (standard)

      can do 0.2- 1.2mg/hr

       
      PO Isosorbide mononitrate 30mg daily starting  
      IV Nitroglycerin Drip   Need intensive BP monitoring (CCU or ICU)
    • Extended Release Isosorbide mononitrate 30mg daily
    •  

    Beta Blockers

    BetaBlockersSummary.png

    Ranolazine

    Drugs:

    Ranolazine

    Mechanism:

    Novel anti-anginal agent.

    Selective inhibition of the late sodium channel.

    Indications:

    - Refractory angina despite optimal BB, CCB, Nitrate therapy.

    - NEW!: One study indicated strong anti-arrhythmic effect.

    Side Effects/Cautions:

    - Prolongues QT interval, and risk of arrhythmias is not clear.

    - Renal disease: use with caution.

    Notes:

     

     

     

    Antiplatelet Agents

    Aspirin

    Drugs:

    ASA 75-162mg/day.

    Mechanism:

    Reduces risk of stroke, MI, vascular deaths in pts with CAD.

      (approx. halfs risk)

    Indications:

    - Indicated for CAD.

      If cannot tolerate ASA, take clopidogrel (plavix)

    - ASA + Clopidogrel = ONLY in recent MI or coronary stent.

    Side Effects/Cautions:

    - Prolongues QT interval, and risk of arrhythmias is not clear.

    - Renal disease: use with caution.

    Notes:  

     

    Clopidogrel


    Drug Mechanism Indications Research
    Clopidogrel

     

       
     

     

       
    Gp IIBIIIA Inhibitors

     

     

    - Studied in setting of ACS, but trials have been generally

    negative --> increased risk of bleeding, no benefit.

    - May be useful not in the ED, but closer to catheterization

      or as an adjunct to baseline medical therapy in refractory

      ischemia.

    Prasugrel

    Antiplatelet therapy that does not

    require initial hepatic conversion to 

    active metabolite.  

    - Faster onset of action.

     

    - Decreases cardiac events in comparison to clopidogrel,

      but at an increased risk of bleeding... hence not used

      very much.

    - Most studied in PCI.

    Ticagrelor

     

       


    ACE Inhibitors

    Drugs:

    In order of discovery:

    - Captopril (1st one, dosed TID, 8hr duration, metallic taste)

    - Enalapril (BID)

    - Ramipril

    - Perindopril

    Mechanism:

     

    Indications:

    - Heart Failure

    - CAD + (DMII or Reduced LVEF or HTN)

      (Reduce CV and all-cause mortality by 15%)

    - Consider in patients with chronic stable angina

    - Reduces rate of decline in GFR in CKD patients (prologues time to dialysis)

    Side Effects/Cautions:

    - Teratogenic, AVOID in pregnancy.

    Trials:

    CONSENSUS (1987) - Enalapril in NYHA IV

    SOLVD Trial (1991) - Enalapril in NYHA II-III

    HOPE Trial (2000) - Ramipril in vascular disease or DMII + one other RF

                                 (No known LV dysfunction!)

     

     

    Anti-Arrhythmics

    • antiArrhythmicChart.png
    • Vaughan-Williams Classification (based on mechanism).

    Vaughan-Williams Classification

    Mechanism of Action

    Examples

    Effect

    Use

    Class IA

    (rarely used)

    Sodium channel blockade, some potassium channel blockade

    Quinidine, procainamide, disopyramide

    Slows conduction and prolongs repolarization

    Preexcited atrial fibrillation, SVT, ventricular arrhythmias

    Class IB

    Sodium channel blockade

    Lidocaine, mexiletine, phenytoin

    Slows conduction in diseased tissues, shortens repolarization

    Ventricular arrhythmias

    Class IC

    Sodium channel blockade

    Flecainide, propafenone

    Markedly slows conduction, slightly prolongs repolarization

    Atrial fibrillation, atrial flutter, SVT, ventricular arrhythmias

    Class II

    β-blockade

    Metoprolol, propranolol, atenolol

    Suppresses automaticity and slows AV nodal conduction

    Rate control of atrial arrhythmias, SVT, ventricular arrhythmias

    Class III

    Potassium channel blockade

    Sotalol, amiodarone, dofetilide, dronedarone

    Prolongs action potential duration

    (COMMON)

    Atrial fibrillation, atrial flutter, ventricular arrhythmias

    Class IV

    Calcium channel blockade

    Verapamil, diltiazem

    Slows sinoatrial node automaticity and AV nodal conduction

    SVT, rate control of atrial arrhythmias, triggered arrhythmias

    A1 receptor agonist

    Adenosinea

    Slows or blocks sinoatrial and AV nodal conduction

    Termination of SVT

    Increasing vagal activity

    Digoxina

    Slows AV nodal conduction

    Rate control of atrial arrhythmias

    AV = atrioventricular; SVT = supraventricular tachycardia.

    aThese agents do not fall into the Vaughan-Williams classification scheme.

     

     

     

     

    • avoid Class II and IV agents in patients with decompensated HF or WPW suspected. (Inhibit conduction through AV node, allow uninhibited condition through accessory pathway).  In setting of AF, can precipirate VF.
    • Class I and III agents - have greater anti-arrhythmic effect.
      • Can cause ventricular arrhythmias (pro-arrhythmia).
      • If structurally normal heart, Class IC medications used for AF/AFL.
        • BUT! contraindicated in CAD, particularly post-MI because increase risk of pro-arrhythmia or polymorphic VT (propafenone, flecanide)
        • Class IC agents can enhance AV nodal conduction, can increase 1:1 conduction, causing very rapid AF.  AV nodal blocker used concurrent
    • Class III agents can be used for ventricular arrhythmias, but can lengthen QT interval (initiated over 3-4 days of inpatient setting) to monitor QT and bradycardic effects.
      • Load these medications. if QT >500ms or incr by >15% or 60ms  --> decrease dosage or D/C drug.
      • Amiodarone i
        • Is preferred agent for HF and LV hypertrophy although has several S/E:
          • Thyroid dysfunction
          • Liver toxicity
          • Pulmonary fibrosis
          • Skin hypersensitivity
        • IV loading can cause hypotension and can prolong QT interval, but low pro-arrhythmic effect, not associated with torsades. 
        • Amiodarone is one of few you dont' have to be in the hospital to start (QT not as much of concern).
        • Monitor:
          • Thyroid function and Liver function q6mo
          • PFT's q1year. (also get DLCO)
      • Dronedarone
        • Newest approved class III agents, reduces hospitalization for cardiovascular events and death in patients with AF/AFL.  
        • Does not have side effect profile of amiodarone.
        • Causes creatinine to go up, but no effect on GFR.
        • Should not be used in patients:
          • NYHA II-III heart failure with recent decompensation or any pt with class IV heart failure.
          • Should not be used as rate control agent in permanent AF due to increased risk of CV events.  (amiodarone is ok for that).
    • Other drugs not included in V-W Classification:
      • Digoxin
        • NaKCL exchange blocker, increases vagal activity to heart.
        • Provides additional inotropic effect in sedentary patients, and AV nodal blocking effect (not as effective in active patients).
      • Adenosine
        • Blocks AV node very rapidy for short time.
        • Terminates re-entry arrhythmias.
        • Often use as a diagnostic or theraputic agent in narrow complex rhythm.
        • Half-live 6 seconds.
    • When loading: if sQTc.

     

    Amiodarone

    Source: CMAJ 2011 "Falling between the cracks: a case of amiodarone toxicity"

     

    • Class III antiarrhythmic
    • Approved in Canada 1986
    • Effects both myocardial depolarization and repolarization.
    • Class III (K+ channel blockade)
      • Also a Class I (Sodium channel blocker), Class II (noncompetitive alpha+beta blocker), and Class IV (CCB)
    • Pharmacology: (quite complex)
      • Metabolized by DEA (active metabolite) by the liver
        • Inhibits CYP P450 1A2, 2C9, 2D6, 3A4
        • P-glycoprotein membrane efflux pump (clears Digoxin)
      • Half-life 56 days
        • Active metabolite has even longer half life. 
      • Very large volume of distribution (66 L/kg)
        • Accumulates in plasma, fat, muscle, lungs, liver, skin etc..
        • High iodine content = unmasks thyroid abnormalities
      • Requires a 10 gram load over 1 week followed by maintenance 100-400 mg/day
      • Bioavailability highly variable (30-80%), more with food
      • +++ Drug interactions (Cyp450 enzymes inhibited and P-glycoprotein efflux transporter)
    • Advantages over other antiarrhythmics based on HRS guideline
      •  1) At 2 years prevents sustained VT/VF or death ~ 60%
      •  2) Minimal negative inotropic effects
      •  3) amiodarone has low pro-arrhythmic potential
      •  4) prospective trial data--> long-term neutral effects on survival and safety in patients post-MI with LV dysfunction, and in patients with dilated cardiomyopathy (ischemic or non-ischemic)
      •  5) More effective than class I drugs
      •  6) the efficacy of amiodarone is similar to ICD therapy if LVEF > 35%
    • Side Effects
      • NOTE: Amiodarone and DEA levels can be measured
        • > 2.5 mg/L = high risk of adverse events
        • > 1.5 mg/L = elevations in liver enzymes likely
      • Risk increases with higher maintenance, cumulative dose
      • Pulmonary toxicity is highest > 200mg/day
      • Many papers cite adverse events based on cumulative dose:
        • >100g = pulmonary toxicity risk
        • >144g = thyroid toxicity
      • Together, risk of adverse effects is 15% at 1yr and 50% at chronic use

     

    System Effect Findings Monitoring Treatment Options

    Pulmonary

    (2%)

    - Pulmonary fibrosis

    - Infiltrates

    - ARDS

    CT - Focal/diffuse opacities

    Decrease DLCO

    - Acute or subacute

      dyspnea

    - Nonproductive cough

     

    - CXR (Baseline + Annually)

    - CT (if clinically suspected

             toxicity)

    - PFTs (baseline

     + if new radiology findings)

    - D/C Drug if can

    - Steroids if severe

    (can continue drug when 

    resolves, Amio+steroid

     if no other option)

    Thyroid

     

    Hyperthyroidism

    (1-23%)

    Wt loss, weakness, 

    goiter, tremor, tachycardia

    Warfarin dose change

    - TSH, T3, T4 (Baseline + q6mo)

      [don't do in first 3 mo]

    - Steroids, PTU or methimazole

    - Consider d/c drug

    - Thyroidectomy

     

    Hypothyroidism

    (4-22%)

    Wt gain, fatigue, dry skin

    - Antithyroid peroxidase

      antibodies  (baseline only)

    L-thyroxine
    Cardiac

    - Bradycardia, AVB

    - Arrhythmias

      - ECG baseline + annual  

    Liver

    (15-30%)

    15-30% -> AST, ALT > 2x ULN

    < 3% --> Hepatitis, cirrhosis

    - AST, ALT baseline + q6mo

    - Decrease dose

    (if severe, then d/c)

    - Hepatitis - exclude other

       causes, biopsy

    GI (30%)

    Nausea, anorexia, Constipation

       
    Ocular

    - Corneal deposits (>90%)

    - Halo vision (<5%)

    - Optic Neuropathy (<1)

    - Vision worse @night

    - Peripheral vision changes

    - Acuity

    - Optho consult only if

      baseline vision problems

     
    Skin

    Blue-Grey Coloration (<10%)

    Photosensitivity (25-75%)

    - Physical Exam

    - Reassure, decrease dose

    - Avoid sun exposure

    - Sun Screen

    CNS

     

    - Peripheral Neuropathy

      (0.3%/yr)

    - Ataxia, tremor,

      poor sleep (3-30%)

    - Tremor (esp during load) - Physical Exam

    - Dose dependent

    - May improve or resolve with

      dose adjustment

     

    • Drug interactions
      • Drug Mechanism Effect

        B-Blockers

        (metoprolol,

        timolol, propranolol)

        Additive B-blockade

        CYP 2D6

        Bradycardia, AV Block,

        Increased BB Effect

        NDHP CCB

        (Diltiazem, Verapamil)

        Additive CCB Effect

        Bradycardia, AV Block

        Increase CCB Effect

        Digoxin P-glycoprotein inhibition Increase dig concentration+effect
        Cyclosporine

        CYP 3A4, and P-glycoprotein

        inhibition

        Increase cyclosporine levels

        Antidepressants

        (SSRI, TCAs)

        Cyp P450 inhibition

        Longer QT

        Increased SSRI/TCA Concentration

        Antibiotics

        (macrolides, Antifungals

        [Azoles], quinolones)

        CYP 3A4, QT prolongation

        Increased concentration

        Longer QT interval

         

        Warfarin CYP 2C9 inhibition Increased warfarin levels (higher INR)

        Simvastatin (HMG-CoA

        reductase Inhibitor)

        CYP 3A4 inhibition Increased statin levels + halflife
    • Monitoring
      • Heart Rhythm Society (HRS) Guidelines
      • Only 11% adherence to this guideline
      • At Baseline:
        • ECG, CXR, AST, ALT, Thyroid (T3, T4, Anti-TPO)  [AntiPTO predicts hypothyroidism]
        • PFTs
        • Physical Exam: Skin, CNS, Derm (optho consult if baseline vision problems)
      • Regular
        • q6mo: TSH, T3, T4, AST, ALT
        • q1yr: CXR, ECG, 
        • Repeat Anti-TPO at 6mo to establish new baseline
      • If Symptoms
        • PFT, CT, CXR, Optho consult, ECG

     

    Thyroid Dysfunction

    Source: HRS 2007 Amio guidelines (attached)

    JCEM Article

     

    • Amiodarone can acutely do:
      • ↑ TSH acutely (usually < 20)
      • ↑ free and total T4
      • ↓ free and total T3
    • Can cause thyroid dysfunction or thyrotoxicosis
    • Amiodarone Induced Hypothyroidism (AIH)
      • Prevalence 22%, usually in first 1-24mo of amio tx. (more common than hyperthyroidism)
      • TSH > 20 mU/L and low or low-normal free T4
      • Majority of patients (who do not have Hashimodo) will resolve their thyroid problems when amio is d/c'ed
      • Treatment:
        • If subclinical, consult endocrine (otherwise, just treat)
        • L-thyroxine until TSH normalized
      • (Consult endocrine if TSH is high and T4 is normal, and pt is asymptomatic - subclinical)
    • Amiodarone Induced Thyrotoxicosis (AIT)
      • Much lower incidence than hypo in iodine sufficient areas
      • Can occur at any time during treatment
      • Lab:
        • TSH suppressed, elevated free T4, elevated or high-normal T3
      • Symptoms
        • Amio has BBlocking properties (so cancels some thyrotoxicosis effects)
        • Wt loss, warfarin dose change
      • Two Types:
        • Type 1: Underlying Graves' disease or multinodular goiter --> iodine load from amiodarone exacerbates disease
        • Type 2: Thyroditis  (tender gland)
        • Often unclear which one underlying
      • Investigations:
        • Can get thyroid U/S (Incr vascularity in Type1, nodules may see in Type 1)
      • Treatment
        • Consult Endocrine (even if TSH mildly suppressed, and subclinical)
        • Antithyroid drugs (PTU or Methimazole)
        • Type 1 (Graves or MNG)
          • D/c amiodarone (although effects will last a LONG time)
          • Treat with HIGH doses of PTU/Methimazole (i.e. 40-60 mg/d methimazole)
            • May take a long time for euthyroid (gland saturated w/ iodine)
            • Sodium perchlorate is sometimes used (added for 2-6w) decreases iodine uptake. (low doses 1g/d or lower to minimize marrow/renal S/E)
          • Radio-iodine ablation will not work (too much iodine), need thyroidectomy if symptomatic (or VT comes back)
        • Type 2 (If Clearly thyroiditis - tender gland, fever):
          • Prednisone (continue amio), 0.5-0.7 mg/kg/d x3mo
            • Dramatic response, 50% cured in 4wk, sometimes delayed
          • Thionamides are NOT EFFECTIVE
          • Eventually, thyroid burns out, and need supplementation.
          • No reason to stop amiodarone (long half-life anyways)
        • If unclear:
          • Common strategy is to continue Amio, and start Prednisone, and anti-thyroid drug (PTU or MTLE)
          • At 1-2 weeks reassess:
            • If prednisone responsive, can d/c PTU/methimazole
      •   Type 1 (thyroid disease)  Type 2 (thyroiditis)
        Underlying thyroid disease YES NO
        CFDS Incr vascularity Absent hypervascularity
        RAIU Low/Normal/Increased Low/Absent
        MIBI Thyroid retention Absent uptake
        Antibody Sometimes Absent
        Remission NO POSSIBLE
        Medical Therapy Thionamides (Plus KClO4) Steroids
    • NOTE: Acutely ill patients thyroid function tests are hard to interpret (euthyroid sick syndrome), consult endo.

    Resources

    • QT prolonging drugs:
      • www.azcert.org
    • Amiodarone
      • CMAJ 2011 "Falling between the cracks: a case of amiodarone toxicity"
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