Transcript When Cardiovascular Medications Become Toxins

When Cardiovascular Medications
Become Toxins
Sami Alsolamy
ICU Fellow
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Objectives
 Discuss the pathophysiology and
pharmacokinetics of digoxin, ß-blockers, and
CCBs.
 Recognize and treat patients poisoned by CV
toxins, based on properties of the specific
agent(s) involved.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Introduction
 Cardiovascular agents
were the fourth most
common
pharmaceutical agent
involved in poisoning
fatalities in the US.
 CCBs ( 60 %), ßblockers (17% ), and
digoxin (17%.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Cardiac Glycosides
 Cardiac glycosides
became widely accepted
as a medical treatment
for heart failure.
 Digoxin,
 Derived from the foxglove
plant
 Is the most commonly pre
scribed cardiac glycoside in
north amarica .
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ß-blockers
 At least 15 different ß-blockers are commonly
used in the North America
 They have proven effective for the treatment of
ischemic heart disease, hypertension, congestive
heart failure, and certain dysrhythmias
 Nonspecific ß- blockers that also block α 1
receptors eg : Labetalol and carvedilol
 Nonspecific ß- blockers that blocks both ß 1 and
ß 2 receptors eg : Propranolol
 Selective for ß 1 receptors eg : metoprolol
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
CCBs
 Due to their negative inotropic and chronotropic
effects, CCBs are used for the treatment of
hypertension, dysrhythmias, and angina.
 10 CCBs approved for clinical use, each belonging
to 1 of 4 classes:
 the phenylalkylamine class (verapamil),
 the benzothiazepine class (diltiazem),
 the diarylaminopropylamine class (bepridil),
 The dihydropyridine class (nicardipine, nifedipine,
isradipine, amlodipine)
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : Digoxin
 Digoxin is typically dosed orally at 0.125 to 0.5
mg/day
 It is well absorbed orally, with a bioavailability
of about 70 to 80%.
 Clarithromycin, erythromycin, and tetracycline
alter gut flora and may lead to elevated serum
levels of digoxin.
 Drugs that decrease absorption, such as
antacids, cholestyramine, metoclopramide,
and neomycin.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : Digoxin….(2)
• Distribution of digoxin
follows a 2-compartment
model
• Followed by a slower
distribution to cardiac
tissue over a period of 6
to 8 hours
Serum peak 2-3 h
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : Digoxin….(3)
• Digoxin is approximately 25% protein-bound.
• It has a volume of distribution in adults of 6 to
7 L/kg
•
Digoxin is metabolized to a very small extent
via hydrolysis, oxidation, and conjugation.
•
About 50 to 70% is excreted unchanged by
the kidney, and dosing should be adjusted
according to the patient’s creatinine
clearance.
• Smaller amounts of the drug are excreted in
bile, with enterohepatic recycling occurring.
•
The elimination half-life ranges from 36 to 51
hours.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : ß-blockers
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : ß-blockers
 Equally important properties, which vary from
one beta-blocker to another, include
cardioselectivity, membrane-stabilizing effect,
lipophilicity, and intrinsic sympathomimetic
activity.
 There is also large variation in the volume of
distribution among ß-blockers
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ISA, intrinsic sympathomimetic activity; MSE, membrane-stabilizing effect
; Vd, volume of distribution; VT, ventricular tachycardia
Hoffman, Robert
S..Goldfrank’s
of Toxicologic
Emergencies
When
CardiovascularManual
Medications
Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : CCBs
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : CCBs
 Onset of action following an oral dose of an
immediate releas preparation usually occurs
within 30 to 60 minutes.
 All CCBs are highly protein-bound, and most
have large volumes of distribution.
 Elimination half-lives range from 1.3 to 64
hours.
 Increased elimination half-life may develop in
the setting of an overdose
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pharmacokinetics : CCBs
Hoffman, RobertWhen
S., Goldfrank’s
Manual of Toxicologic Emergencies
Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology: Digoxin
Increase
in vagal
tone
Inhibits
the Na / K
ATPase.
(1) increasing the force of myocardial contraction to increase cardiac output
(2) decreasing atrioventricular (AV) conduction to slow the ventricular rate i..
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology: Digoxin
Block SA
and AV
node
Paralyzes
the Na-K
pump,
Increase cardiac
automaticity,
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Digoxin : ECG
Atrial fibrillation with slow, regular ventricular
rate (AV dissociation).
 Nonparoxysmal junctional tachycardia (rate 70–
130 beats/min).
 Bidirectional ventricular tachycardia
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology : ß-blockers
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology
GDP
cAMP: augments myocardial contraction , enhances cardiac
conduction , and accelerates heart rate .
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
 Complex beta2 effects include vascular
(smooth muscle relaxation and vasodilation)
and liver (glycogenolysis, gluconeogenesis).
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Propranolol
 Propranolol's toxicity derives from its
lipophilic nature and membrane-stabilizing
effect that allow it to penetrate the CNS,
leading to obtundation, respiratory
depression, and seizures.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Sotalol : Potassium Channel Blockade
 Sotalol is a nonselective antagonist that is
unique because of its ability to block the
delayed rectifier potassium current (I Kr )
responsible for repolarization.
 This prolongs the action potential duration
and is manifested on the electrocardiogram
by a prolonged QTc.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology: Calcium channel
blockers
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology : CCB
Phase 2 (plateau phase )
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Pathophysiology : CCB
 Reduce cardiac contractility, depress SA nodal
activity, and slow AV conduction
 In smooth muscle, CCBs cause vasodilation and
lead to hypotension.
 Each group binds a slightly different region of the
calcium channel and thus has different affinities
for the various L-type calcium channels both in
the myocardium and the vascular smooth
muscle.
 Nifedipine overdose more commonly causes
reflex sinus tachycardia from peripheral
vasodilation.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ICU Managements
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ICU Management: Digoxin
Acute Vs Chronic
Marx: Rosen's Emergency Medicine, 7th ed
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ICU Management: Digoxin
 Serum digoxin level.
 It must be interpreted in relation to the clinical
condition of the patient, the relationship of the
time of obtaining the blood sample to that of the
last dose and metabolic abnormalities.
 - It is inaccurate to use the therapeutic range of
digoxin of 0.5– 2.0 ng/mL as the sole indicator of
toxicity. In general, patients with pharmaceutical
digoxin toxicity have clinical findings and mean
serum concentrations above 2 ng/mL, measured at
least 6 hours postingestion for digoxin.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ICU Rx :Digoxin (3)
 There is no evidence to support gastric
emptying for the treatment of digoxin
overdose
 Multidose charcoal has historically been used for
digitoxin toxicity because of its prominent 6%
enterohepatic circulation.
Antman EM, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments:
Final report of a multicenter study. Circulation 1990; 81:1744
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Fab Fragments (Digibind or Digifab)
Intravascular
Interstitial space
1- Bind intravascular free digoxin
When Cardiovascular Medications Become Toxins
3- A concentration gradient is then
established to facilitate movement of
digoxin that is dissociated
from its binding sites
Sami Alsolamy
7/17/2015
Fab Fragments (Digibind or Digifab)
Hoffman, Robert S..Goldfrank’s Manual of Toxicologic Emergencies
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Cont…
 Electrolyte Correction: K , Mg and Na
 Atropine is generally used for severe bradycardia
and advanced AV block.
 Pacing:
 Transvenous pacing: may induce ventricular
tachydysrhythmias in a myocardium made irritable by
digitalis
 Cardioversion
 Can cause asystole.
 Phenytoin and lidocaine are the safest of the
antidysrhythmic drugs for controlling
tachydysrhythmias
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ICU Managements: Beta-adrenergic
blockers
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Rx B.B : Hypotension and Bradycardia
Catecholamines less
effective : higher doses
are usually needed
Glucagon : Acts by
stimulating adenylate
cyclase
GDP
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Rx B.B : Hypotension and Bradycardia
 The first step in the treatment of beta-blocker
overdose : atropine, glucagon, and crystalloid
fluids.
 A dose of atropine may quickly wear off or be
ineffective, so infusion of more potent drugs or
cardiac pacing is usually necessary.
 Glucagon: because of its short (20-minute) halflife, an infusionshould be started immediately after
the bolus.
Taboulet P, et al: Pathophysiology and management of self-poisoning with beta-blockers. Clin Toxicol 1993; 31:531.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Rx B.B : Hypotension and Bradycardia
 Insulin and Glucose
 high-dose insulin infusion (in combination with
glucose administration to maintain serum glucose
levels) has been reported to improve outcomes
 The mechanism of action is via the positive
inotropic effects of insulin.
 Inotropes and chronotropes
 Isoproterenol, Dopamine, or Epinephrine
 : Higher doses are usually needed
Holger JS, Engebretsen KM, Fritzlar SJ, et al: Insulin versus vasopressin
and epinephrine to treat beta blocker toxicity. Clin Toxicol 2007; 45:396.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Rx B.B : Hypotension and Bradycardia
 Refractory cases of bradycardia
 external or transvenous pacemaker
 Phosphodiesterase inhibitors such as, amrinone
and milrinone.
 Raise intracellular cyclic AMP levels and stimulate
contractility
 Hypotension secondary to peripheral vasodila tion
 Intraaortic balloon pump or extracorporeal
circulation
Tsuji Sato, Okubo N, Naito H: Milrinone versus glucagon: Comparative hemodynamic effects in canine propranolol poisoning. Clin Toxicol 1994; 32:277.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
ICU Managements: Calcium channel blockers
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Hypotension and Bradycardia
 Atropine
 Calcium
- Lead to increase the extracellular Ca 2+ concentration, which increases
the transcellular concentration gradient, driving Ca 2+ intracellularly
- Poor effect on peripheral vasodilation
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Rx CCB : Hypotension and Bradycardia
 Inotropes and Vasopressors
 Norepinephrine appears to be an appropriate
initial catecholamine to use in hypotensive CCBpoisoned patients*
 Insulin and Glucose
 animal evidence
* Buckley NA, Whyte IM, Dawson AH: Overdose with calcium channel blockers [letter]. BMJ 1994; 308:1639.
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Hemodialysis
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Hemodialysis
CCBs:
- Large volume
- Hige plasma protein binding
 Optimal drug characteristics for removal:





Relative molecular mass < 500
Water soluble
Small Vd
Minimal plasma protein binding
Single compartment kinetics
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
?
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Hemofiltration
 Hemofiltration is useful for removal of
substances with :
 Large volume of distribution
 Hemofiltration membranes are permeable to
substances weighing up to 20,000 d.
Brett AS, Rothschild N, Gray R, et al. Predicting the clinical course in intentional drug overdose: implications for the use of the intensive
care unit. Arch Intern Med 1987; 147:133–137
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015
Hemoperfusion
 Drug clearance is not limited by:
 Low water solubility,
 High molecular weight
 Increased protein binding
 But need central compartment
Rommes JH. Haemoperfusion, indications and side-effects. Arch Toxicol 1992; 15:S40 –S49
When Cardiovascular Medications Become Toxins
Sami Alsolamy
7/17/2015