Transcript Cardiac Contractility

Cardiac Contractility
Dapo Odujebe, MD
Toxicology Fellow
NYC Poison Control Center
Overview

Review & Cases

Cardiac Electrophysiology

Cardiac Contractility

Cardiac Medications
• Overdose Management

Questions?
Case #1



45-year old woman PMHx s/f depression
presents to the ED after allegedly
ingesting all of her anti-HTN medication.
Prescription filled 3 days prior for 30
tablets of diltiazem CD 240 mg.
Patient alert & oriented, mildly diaphoretic
and complaining of generalized weakness.
Case #1

Vital signs:
• BP: 76/36, HR: 46, RR: 14, Temp: 98.6
• pOx: 100% RA, AccuChk: 154


Rest of physical examination is benign.
Patient placed on a cardiac monitor, O2 via
nasal cannular and IV access established.
Case #1

What is the next step in her management?
Case #3



An 86-year old woman presents with increased
confusion and vomiting.
Per family, she’s had increasing weakness,
nausea & anorexia over the last 3 days.
PMHx:
• hypertension
• congestive heart failure
(CHF)
• diabetes mellitus

Medications:
•
•
•
•
•
hydrochlorothiazide
digoxin
furosemide
enteric-coated aspirin
metformin
Case #3



In the hospital, she is alert, but oriented only to
person.
Vital signs are normal, except for a heart rate of
46 beats/minute. She weighs 143 lbs (65 kg).
Her physical examination demonstrates:
• bibasilar rales
• irregular S1, S2 with a S3 gallop
• bilateral LE 2+ pitting edema, up to her shins
Case #3

ECG:
• atrial flutter with variable block
• ventricular rate of 40-50 beats/minute with occasional
premature ventricular contractions (PVCs).

Laboratory results were within limits except:
• potassium - 3.2 mEq/L
• creatinine - 1.6 mg/dL
• glucose - 235 mg/dL

Initial digoxin serum concentration (SDC):
• 3.4 ng/mL (> 6 hours since last dose).
Case #3

What is the next step in her management?
Cardiac Electrophysiology
Cardiac Electrophysiology

Actions potentials
• SA node
• Cardiac muscle


(atria, ventricles & Purkinje fibers)
Channels
• Ca2+ channel
• β-adrenergic receptor
• Na+/K+-ATPase
Pacemaker Cell Cycle
Phase 0
Phase 3
0 mV
-50 mV
-70 mV
Phase 4
Ca2+
Phase 4
Action potential (SA Node)
Pacemaker of the heart
 Unstable resting potential

• Exhibits automaticity
• AV node & His-Purkinje system are
latent pacemakers

Phase 1 & 2 are not present in
pacemaker action potentials
Cardiac Muscle Cell Cycle
Phase 0
Phase 1
Phase 2
+30 mV
0 mV
Ca2+
Phase 3
-70 mV
-90 mV
Phase 4
Resting Potential
Na+
channel
Voltage dependent
L-type Ca2+ channel
2
Na+/K+ ATPase
K+
3 Na+
K+ channel(s)
Ca2+
3 Na+
β-adrenergic receptor
Na+/Ca2+ exchanger
SR (Mitochondria)
Heart muscle
Ryanodine receptor
Na+/K+ ATPase
Na+/Ca2+ Antiporter
Representative Cardiac Cell
Cardiac Contractility
Contractility

Intrinsic ability of cardiac muscle

Also called ‘inotropism’ or ‘inotropy’

Related to the intracellular [Ca2+]

Inotropic agents
• positive: increase contractility
• negative: decrease contractility
Factors Increasing Contractility

Increased intracellular [Ca2+]
• increased heart rate
• cardiac glycosides (e.g. digoxin)

Stimulation of β1-adrenergic receptor
• sympathomimetic agents
• catecholamines
Contractility - Other Factors

Chronotropy
• rate of contraction
• also affected by intracellular [Ca2+]

Dromotropy
• rate of impulse conduction
• noted particularly at AV node
Cardiac Medications &
Receptors
Cardiac Medications

Some examples:
• Ca2+ channel antagonists/blockers
• β-adrenergic antagonists/blockers
• Cardiac glycosides (digoxin)
2+
Ca
Channel Antagonists
Calcium Channel

Cardiac calcium channels
• L-type calcium channel
• ryanodine (RyR2) calcium channel


located on the sarcoplasmic reticulum
Critical for:
• conduction velocity (AV node)
• duration of depolarization
• cardiac muscle contraction
Ca2+ Channel Antagonists

Block the L-type calcium channel
• negative inotropy in cardiac muscle

decrease available intracellular Ca2+
• negative chronotropy in pacemaker cells
• negative dromotropy at the AV node
• relaxation of vascular smooth muscle
decreased afterload
 decreased systemic blood pressure
 increased coronary vascular dilatation

Ca2+ Channel Antagonists

Phentylalkylamines
• e.g. verapamil

Benzothiazepines
• e.g. diltiazem

Dihydropyridines
• e.g. nifedipine

Diarylaminopropylethers
• e.g. bepridil

Tetralene Derivatives
• e.g. mibefradil
Ca2+ Channel Antagonists

Overdose of CCB
• extension of therapeutic effects

Lose their selectivity (mostly)
• Negative inotropy (bradycardia)
• Negative chronotropy (hypotension)
• Vasodilation (hypotension)
• Negative dromotropy (AV blocks, brady)
• +/- hyperglycemia (depressed insulin)
CCB = calcium channel blocker
β-Adrenergic Antagonists
β-Adrenergic Receptors


There are 3 known subtypes of βadrenergic receptors, namely β1, β2
& β3.
The human heart has predominantly
β1 receptors
• β2 & β3 exist in ‘small’ quantities
β-Adrenergic Receptors

Stimulation on β1 receptors
• increases
• increases
• increases
• increases

heart rate
contractility
conduction velocity
automaticity
The effect of adrenergic agents on
the heart is mediated through a
secondary messenger – cAMP
β-Adrenergic Receptors

Intracellular cAMP concentrations are
regulated by 3 components:
• adrenergic receptor on the cell surface
• a “G-protein” complex
• adenyl cyclase – enzyme synth. cAMP

cAMP acts as a secondary messenger
• interacts with protein kinase A to
increase phosphorylating activity
β-Adrenergic Receptors


Protein kinases transfer a phosphate
group from ATP to serine
Thereby, phosphorylating various
cellular proteins
• phospholamban ( activity)
• troponin ( activity)
• L-type calcium channels ( activity)
β-Adrenergic Receptors
Bers DM. Cardiac excitation-contraction coupling. Nature 2002 415;198 - 205
β-Adrenergic Antagonists

β-Adrenergic antagonists
• effects similar to blockade of L-type
calcium channel

Clinical effects
• decrease contraction (hypotension)
• decrease chronotropy (bradycardia)
• decrease dromotropy (AV blocks, brady)
β-Adrenergic Antagonists

Extra-cardiac signs of toxicity
• neurological disturbances

drowsiness, non-agitated coma
• dilated pupils
• respiratory depression

Treatment of toxicity is based on:
• stimulation of glucagon receptor
• restoring intracellular Ca2+ stores
Overdose Management
Overdose Management

Decontamination
• Emesis not recommended
• Activated charcoal should be considered
• Gastric lavage with 36-40 Fr tube

contraindicated in patients w/ bradycardia

consider particularly in patients a/ SR preps
• Whole bowel irrigation

particularly a/ SR preps
Overdose Management

Atropine
• Adult: 0.5 – 1.0 mg IVP (max 3 mg)
• Children: 0.02 mg/kg IVP
• given every 2 – 3 minutes

Should be held in patients getting WBI because
of anticholinergic effects
Overdose Management

Calcium salts
• increases extracellular Ca2+
• calcium gluconate: 1 gm = 4.3 mEq
• calcium chloride: 1 gm = 13.4 mEq

Dose
• 10 – 20 mL of 10% CaCl2
• 30 – 60 mL of 10% Ca gluconate
Overdose Management

Dose (cont’d)
• effect is transient, redose q15 – 20 mins
• in adults, can give 50 mL of 10% CaCl2
(5 gm) before having to check a Ca2+
serum concentration
• (i.e. 150 mL of 10% Ca gluconate)
• CaCl2 is causes sclerosis of peripheral
veins and should be given centrally
Overdose Management

Glucagon
• activates adenyl cyclase directly via
glucagon receptor
• adult dose: 2-5 mg slowly IV
• can be repeated every 5-10 minutes
• total dose should not exceed 10 mg
• follow bolus with an infusion of the dose
that produced an effect
Overdose Management

Catecholeamines
• attempt to competitively antagonize βadrenergic antagonist at the receptor
• no convincing evidence
• chance of stimulating other receptors in
the required dose to produce competive
displacement
• if one is used – norepinephrine is
probably the best choice
Overdose Management

Insulin & Glucose
• growing evidence that used correctly,
this increases inotropy and chronotropy
• theory: improved Ca2+ entry &
improved myocardial carbohydrate use
• Dose: 0.5 – 1 Unit/kg/hr regular insulin
• give 0.5 gm/kg/hr dextrose (glu > 100)
• check glucose every 30 mins initially
Overdose Management

Amrinone
• inhibits breakdown of cAMP by
phosphodiasterase III
• thereby increasing intracellular [] of
cAMP
• this increases inotropy and chronotropy
• BUT, causes vasodilation & hypotension
• should be used with a vasopressor
Cardiac glycosides
(digoxin)
Therapeutic



Digoxin inhibits Na+/ K+-ATPase
This increases cytosolic Ca2+ which
increases inotropy.
Therapeutically:
• digoxin increases automaticity
• shortens the repolarization intervals of
the atria and ventricles
Therapeutic


Decreases depolarization & conduction
through the SA and AV nodes.
These changes are reflected on ECG by:
•
•
•
•
decrease in ventricular response rate
PR interval prolongation
QT interval shortening
ST segment & T-wave opposite major QRS
forces


scooped ST segment
Both these effects result in the characteristic
“digitalis effect”
Therapeutic
Digitalis effect
Atrial flutter with PVC

Some characteristic signs of digoxin therapy and
toxicity.
Clinical Toxicity
Toxicologic

Effects mirror its therapeutic actions.
• Bradydysrhythmias

(from increased VAGAL TONE)
• Ventricular tachydysrhythmias

(from myocardial “irritability”)
• Rapid atrial rhythms with slow
ventricular response

(slowed AV conduction)
2 K+
Phase 2
3 Na+
Ca2+
Ca2+
3 Na+
Ca2+
Ca2+
Ca2+
SR (Mitochondria)
Ca2+ Ca2+
Ca2+
Ca2+
Cell Electrophysiology
= DigoxinDigoxin
K+
2 [K+]
Phase 2
3 [Na+]
Ca2+
Ca2+
2+
Ca
2+
Ca2+2+
Ca
2+
Ca 2+
Ca 2+ 2+
2+
Ca
Ca
CaCa
2+ 2+
Ca2+
Ca2+2+ CaCa
2+
Ca 2+ 2+Ca2+
2+
2+ Ca
Ca Ca
CaCa
2+
2+
Ca
Ca
2+
2+
Ca
Ca
2+
Ca
2+
Ca
2+
2+
Ca
Na+
SR (Mitochondria)
Ca
Therapeutic & Toxic MoA
Signs of Toxicity

Metabolic
• Acute: Hyperkalemia is a marker for severe
poisoning
 Due to blockade of Na+/K+ ATPase
 Increases AV blockade and worsens
bradydysrhythmias
• Chronic: Hypokalemia predisposes the patient
to dysrhythmias at lower digoxin levels
 Higher resting potential increases
automaticity
Signs of Toxicity

Cardiac
• Acute or chronic


Increased automaticity with high-degree AV
block
Any dysrhythmia possible…..
… EXCEPT a rapidly conducted
supraventricular rhythm.
Electrocardiogram

PVCs (most common dysrhythmia)

Classic ECG findings:
• Bidirectional ventricular tachycardia
• Atrial tachycardia with variable or slow
ventricular response
• Accelerated junctional rhythms
Overdose Management
Management of Toxicity


The main goal of treatment is to
correct cardiac toxicity.
Treatment of cardiac toxicity
usually leads to resolution of CNS
and GI symptoms.
Treatment

Decontamination
• Activated charcoal (AC)
Adsorbs digoxin well
 Decrease absorption
 ‘Gut dialysis’


[Boldy DA. et al. 1985, de Silva HA. et al. 2003, Ibanez C. et al.
1995]
• Multi-dose AC
Renal failure
 Yellow oleander poisoning

Treatment

Dysrhythmias
• Tachy

Replace K+ or Mg++
Consider Class IB & III antidysrhythmics
• amiodarone, lidocaine or phenytoin for ventricular
dysrhythmias

AVOID Class IA, IC, II and IV antidysrhythmics
• particularly procainamide and quinidine

AVOID cardioversion in TOXICITY
• Brady

Atropine
AVOID transvenous/internal pacing
Management of Toxicity

GI decontamination
• Decrease absorption
• ‘Gut dialysis’
• [Boldy DA. et al. 1985, de Silva HA. et al. 2003, Ibanez C. et al.
1995]

Atropine

Correct electrolyte abnormalities

Consider lidocaine or phenytoin
• for control of dysrhythmias (if definitive
therapy unavailable)
Indications for digoxin-Fab

Symptomatic bradydysrhythmias

Ventricular dysrhythmias

Acute digoxin toxicity & [K+] >5 mEq/L

Ingestion >4 mg - child (or 0.1 mg/kg)

Ingestion >10 mg - healthy adult

SDC of ≥10 ng/mL steady state
• 4-6 hours after ingestion

SDC of ≥15 ng/mL at any time
Chronic Digoxin Toxicity



More common and more controversial
No absolute indication based on serum
concentration
Administer digoxin-Fab if
• ECG evidence of digoxin toxicity
• Unable to tolerate symptoms of toxicity
• Unable to clear digoxin (BUN/Creat)
Management

Empiric Therapy
Acute toxicity:
• Adults: 10 – 20 vials
• Children: 10 – 20 vials

Chronic toxicity:
• Adults: 3 – 6 vials
• Children: 1 – 2 vials
**Should be administered IV over 30 minutes
• via a 0.22-micron membrane filter.
** Can be given as an IV bolus in a critically ill patient
• (per manufacturer).
Management
Ingested Dose Known
amt ingested (mg) x 0.8
# of vials =
0.5
Serum Drug Concentration (SDC) Known
SDC (ng/mL) x pt wgt (kg)
# of vials =
100
Things Not To Do!!


Calcium
• “stone heart” in animal models
Transvenous pacing
• Taboulet et al. 1993
• failure rate of 23% and a 17% mortality
• increased risk of dysrhythmic death
Case Review
Case #1



45-year old woman PMHx s/f depression
presents to the ED after allegedly
ingesting all of her anti-HTN medication.
Prescription filled 3 days prior for 30
tablets of diltiazem CD 240 mg.
Patient alert & oriented, mildly diaphoretic
and complaining of generalized weakness.
Case #1

Vital signs:
• BP: 76/36, HR: 46, RR: 14, Temp: 98.6
• pOx: 100% RA, AccuChk: 154


Rest of physical examination is benign.
Patient placed on a cardiac monitor, O2 via
nasal cannular and IV access established.
Case #1

What is the next step in her management?
Case #3



An 86-year old woman presents with
increased confusion and vomiting.
Per family, she complained of increasing
weakness, nausea and decreased appetite
over the last 3 days.
She has barely kept any of her
medications down, and has not been
eating.
Case #3

PMHx:
• hypertension
• congestive heart failure (CHF)
• diabetes mellitus

Medications:
•
•
•
•
•
hydrochlorothiazide
digoxin
furosemide
enteric-coated aspirin
metformin
Case #3



In the hospital, she is alert, but oriented
only to person.
Vital signs are normal, except for a heart
rate of 46 beats/minute. She weighs 143
lbs (65 kg).
Her physical examination demonstrates:
• bibasilar rales, irregular S1, S2 with an S3
gallop
• bilateral lower extremity 2+ pitting edema up
to her shins
Case #3

ECG:
• atrial flutter with variable block
• ventricular rate of 40-50 beats/minute with occasional
premature ventricular contractions (PVCs).

Laboratory results were within limits except:
• potassium - 3.2 mEq/L
• creatinine - 1.6 mg/dL
• glucose - 235 mg/dL

Initial digoxin serum concentration (SDC):
• 3.4 ng/mL (> 6 hours since last dose).
Case #3

What is the next step in her management?
Digoxin-Fab Dose
Serum Drug Concentration (SDC) Known
SDC (ng/mL) x pt wgt (kg)
# of vials =
100
3.4 ng/mL x 65 kg
100

= 2.21 vials
≈ 3 vials
Always round UP whatever answer you get.
Case #3


The patient is given 3-vials of digoxin
specific antibody fragments (digoxin-Fab).
About 60 minutes after therapy:
• her heart rate improved to 85 beats/minute
• blood pressure remained stable
• her ECG demonstrated

rate-controlled atrial fibrillation with no ectopy
• Her serum potassium concentration had also
improved
Questions?