ACES: CV Drugs / Pesticides

transcript

20 November 2013

CHAPTER 150

CHAPTER 161

CV Drug Toxicity

Pesticides

1. Which of the following poisoning-

antidote therapeutic pairings is correct?

A.Anticholinergic-atropine

A.Beta-blocker- octreotide

A.Calcium-channel blocker-insulin

A.Digoxin-Calcium

2. A 70 year-old patient with a history of CHF on digoxin

presents with weakness. Which is correct with regard to

her EKG?

A. EKG findings suggest the emergent need for

digiFAB

B. EKG findings are most likely due to ischemia

C. EKG findings are expected with therapeutic

digoxin levels.

D. EKG findings are diagnostic of chronic vs. acute

digoxin toxicity

3. A 29 year old patient is brought in to the ED

by EMS in full cardiac arrest. The medics found

an empty bottle of digoxin next to his bed.

What is the most appropriate initial dose of DigiFab for this patient?

A. 2 Vials

B. 4-6 Vials

C. 10 Vials

D. 20 Vials

E. It needs to be calculated

based on the digoxin level.

4. Which of the following is correct

regarding Beta Blocker overdose?

A. Beta blocker overdose universally causes

AV block.

B. Seizures and obtundation are seen more

often with propanolol compared to

metroprolol.

C. Octreotide is an important component of

treatment

D. Unlike calcium channel blocker toxicity,

high-dose insulin/glucose is not effective for beta-blocker toxicity.

5. High dose insulin treatment in beta-blocker overdose increases

cardiac output primarily by increasing heart rate.

• A. True

• B. False

6. Which is correct regarding the EKG? • A. This EKG shows a common finding in acute digoxin

toxicity.

• B. Salvage treatment should include administering of intravenous lipid emulsion (ILE).

• C. This EKG is highly suggestive of Class I sodium channel blockade (TCA, beta blocker (sotalol)

• D. This EKG is diagnostic for Digoxin Toxicity

7. Which statement is not correct with regard

to the theoretical mechanism-of-action of

intravenous lipid emulsion (ILE) therapy for

beta blocker overdose?

A. Directly activates cardiac calcium

channels.

B. Acts as a “sink” for lipid-soluble beta

blockers

C. Provides a substrate for cardiac myocytes.

D. Activates Adenyl cyclase by a C-AMP

process.

E. It would be appropriate to use in a massive

propanolol overdose.

8. Which calcium channel blocker has the highest fatality rate after

overdose? • A. Diltiazem

• B. Verapamil

• C. Nifedipine

• D. Nicardipine

• E. Bepridil

9. Which is correct regarding the clinical endpoint for atropine administration in

Organophosphate toxicity?

A. Pupillary dilatation @ 10mm is the best endpoint.

B. Heart rates exceeding 140 are a relative contraindication to continued atropine administration.

C. Drying of airway secretions is always the best clinical endpoint.

D. Total bolus dosing should never exceed 200 mg .

10. Which is true with regard to intubation of a patient with a significant

organophosphate exposure?

• A. Succinylcholine in OGP is associated with malignant hyperthermia.

• B. Succinylcholine will cause a worsening of airway secretion production.

• C. Succinylcholine is contraindicated in OGP.

• D. Succinylcholine’s activity lasts longer than that of rocuronium.

• E. There is little risk of exposure to ED staff during airway management.

Which painting does not have any connection to a cardiotoxic

medication? A.

1. Which of the following

poisoning-antidote therapeutic pairings is correct?

A.Digoxin-Calcium

1. Which of the following

poisoning-antidote therapeutic pairings is correct?

A.Digoxin-Calcium

Which painting does not have any connection to a cardiotoxic

medication? A.

Cardiovascular Drugs

David E. Slattery, MD

Digoxin Toxicity

• Derived from Digitalis lanata (Foxglove plant)

• Drug looking for an indication

– 1797

• Most common cause of preventable iatrogenic cardiac arrests

Na/K ATPase & Ca2+ exchanger

Pharmacologic Effects

• Inotrope

– Increased contractility due to increase intracellular calcium concentrations

• Parasympathomimetic

– Decreased AV Conduction

– Due to increased vagal efferent activity

– Slowed ventricular rate in afib

Digoxin at Toxic levels

• Paralysis of Na/K ATPase

– Hyperkalemia

• SA Nodal blockade

• AV nodal blockade

• Increased sensitivity of SA node to catecholamines

Digoxin effects on Pukinje fibers

• Decreased resting potential (slowed phase 0)

• Decreased action potential duration

– Increased sensitivity to electrical stimuli

• Enhanced automaticity (increased phase 4 repolarization)

Most common manifestation of Digoxin toxicity= Increased PVC’s

NB! Digoxin can produce any dysrhythmia or conduction block

Digoxin Toxicity

• Elimination half-life

– Digoxin=36 hours; multi-dose charcoal not effective

– Digitoxin=7 days; multi-dose charcoal very effective

• Highly protein bound

– Dialysis is not effective

her EKG?

digiFAB

digoxin levels.

D. EKG findings are diagnostic of chronic vs.

acute digoxin toxicity

her EKG?

digiFAB

digoxin levels.

D. EKG findings are diagnostic of chronic vs.

acute digoxin toxicity

EKG - Digoxin • Causes increased automaticity with

conduction block (PAT with block)

• Therapeutic levels may cause – T wave depression

– ST down sloping (Salvador Dali moustache)

– QT shortened

• Toxic levels – PVCs (most common dysrhythmia)

– Sinus / AV node blocks

– AV dissociation

– SVT (especially with blocks)

– Sinus bradycardia

Paroxysmal Atrial Tachycardia with Block

Aflutter with block

Clinical Manifestations

• Acute Toxicity: – GI: Nausea and vomiting – CNS: Headache, dizziness, confusion, coma – Cardiac: bradyarrhythmias SVT with block – Electrolytes- potassium elevated

• Chronic Toxicity – Hx: elderly patients taking diuretics – GI: nausea and vomiting – Cardiac: Almost any arrhythmia, Ventricular are

common. – Potassium normal or low

Elderly patient with altered mental status and cardiac arrhythmia

• Think Digoxin toxicity

Putting it all together

http://manicgrandiosity.blogspot.com

NB! Indications for Fab Fragments

• Ventricular dysrhythmias (beyond PVC’s)

• Hemodynamically significant bradycardia unresponsive to atropine

• Potassium >5.0

• Worsening rhythm disturbances/rapidly rising K+

A. 2 Vials

B. 4-6 Vials

C. 10 Vials

D. 20 Vials

A. 2 Vials

B. 4-6 Vials

C. 10 Vials

D. 20 Vials

Calculation of DigiFab dosing

• Step 1: Calculate total body-load (TBL)

– TBL= amt ingested (mg) x 0.80

– TBL= dig level (ng/ml)x 5.6 x wt (kg)

Step 2: Calculate # vials of DigFab

1 vial=40 mg DigFab

Number of vials= TBL/0.5

Simple math!

# Vials = Dig level (ng/ml)X wt (kg) 100

Empiric Administration

• Acute with indications

– 10 vials over 30 minutes

• Chronic

– 4-6 vials

• Cardiac arrest

– 20 vials undiluted IV bolus

Digoxin Toxicity Treatment

• IV Access • Continuous monitoring • Activated Charcoal • Bradyarrhythmias

– Atropine – DigiFAB – Pacing (external; avoid transvenous pacing) –

• Ventricular arrhythmias – Digifab – Magnesium – Lidocaine (1-1.5 mg/kg IV bolus followed by 1-4 mg/min) and/or phenytoin (15-20 mg/kg)

Summary

• Think of dig toxicity in any patient with GI or visual disturbances and new onset dysrhythmia or conduction abnormality

• Use DigFab before pacing or other antidysrhythmics

• Hyperkalemia best definitively treated with digfab

4. Which of the following is

correct regarding Beta Blocker

overdose?

AV block.

metroprolol.

C. Octreotide is an important component of

treatment

4. Which of the following is

correct regarding Beta Blocker

overdose?

AV block.

metroprolol. C. Octreotide is an important component of

treatment

Beta Blocker toxicity

• Initially used to treat dysrhythmias

• Antihypertensive effects discovered later

• Used for – SV dysrhythmias

– HTN

– Angina

– Thyrotoxicosis

– Migraine

– Glaucoma

Pathophysiology

• Competitively inhibit endogenous catecholamines at beta-adrenergic receptors.

• Beta 1 blockade – Blocks inotropy, dromotropy (conduction)

chronotropy

• Beta 2 blockade – Blocks Vascular smooth muscle relaxation and

vasodilation

– Inhibits gluconeogenesis

– Inhibits release of Free fatty acids

Unique Characteristics.

• Cardioselctivity (atenolol, metoprolol, esmolol= lower mortality in OD)

• Membrane stabilization (Na channel blockade)

• Lipophilicity

• Intrinsic sympathomimetic

Glucagon MOI

Beta Blocker Pharmacokinetics

• Rapidly absorbed

• Peak effect 1-4 hours

• Hemodialysis not effective except for “ANTS”

– Acebutolol

– Atenolol

– Nadolol

– Timolol

– Sotalol

Manifestations of complications

• Bradycardia and Hypotension

• Unconscious

• Respiratory arrest

• Hypoglycemia (uncommon in adults)

• Others: seizures, VT/VF, mild hyperkalemia

Propanolol

• Non-selective

• Most fatalities

• Lipophilic and readily crosses BB barrier

– Altered mental status

– Seizures

• Hypoglycemia common in children

Sotalol

• Class III (K ch) and Class II (beta blockers) antidysrhythmic

• Torsades de pointes

• Dialyzable (Remember ANTS)

• QT prolongation

– Sotalol

– Acebutolol

Treatment • Phase I:

– Fluids – Atropine – Calcium – Glucagon

• Phase II: – High-dose insulin/glucose (inotrope) – Glucagon – Pressors (epi, NE, isoproterenol) – Consider dialysis of lipophilic beta blockers – Pacing /SWAN-Ganz

• Phase III: Salvage – Intravenous fat emulsion – IAB pump – LVAD

Glucagon

• Inotropic and chronotropic effects not dependent on beta receptors

– Stimulates C-AMP

• Helps counteract hypoglycemia

• Dose: 5-10 mg IV bolus (0.1 mg/kg)

– Followed by response dosing (over 1 hour)

– Short half-life (20 minutes)

• Less effective than insulin-glucose

cardiac output primarily by increasing Heart rate.

• A. True

• B. False

• A. True

• B. False

• A. True

• B. False

High Dose Insulin-Glucose

• HDI is a potent inotrope – Optimizing of the use of carbohydrates

– And modulation of IC calcium

• NB! Improve in CO due more to increase in stroke volume vs. HR

• 1U/kg Bolus

• 1 -10 U/kg/hr drip

• Preceded with amp D50 and followed by D10 or D25 drip.

Adjuncts for specific agents

• Sodium Bicarb

– Use for QRS widening

• Propanolol

• Sotalol

• Magnesium

– Prolonged QT interval

• Sotalol

• Acebutelol

toxicity.

Bi-directional Ventricular Tachycardia Rare but specific for dig toxicity

channels.

blockers

process.

E. It would be appropriate to use in a massive

channels.

blockers

process. E. It would be appropriate to use in a massive

Intravenous Fat emulsion

• Lipid sink

• Optimization of cardiac metabolism

– Provides substrate for myocytes

– Free fatty acids

• Direct activation of cardiac calcium channels

• Dose: 1.5 ml/kg 20% solution over 3 minutes, then drip at 0.25ml/kg/min

Calcium channel blocker toxicity

• Earliest

– Verapamil Nifedipine

• Many indications

– Antihypertensive

– SV tachy

– Hypertrophic cardiomyopathy

– Migraine prophylaxsis

Calcium channel blockers

• Rapidly absorbed

• Peak effect earliest with nifedipine

• Highly protein bound not conducive to dialysis

• B. Verapamil

• C. Nifedipine

• D. Nicardipine

• E. Bepridil

• B. Verapamil

• C. Nifedipine

• D. Nicardipine

• E. Bepridil

Pathophysiology

• Block slow L-type calcium channels

– Coronary and peripheral vasodilation

– Reduction of contractility

– Slow AV conduction

• NB! Verapamil

– Deadliest, severe vasodilation and myocardial depression

Calcium channel blocker toxicity

• Hypotension • Bradycardia • All degrees of AV block • Nifedipine (Dihydropyridines)

– Reflex tachycardia

• No QRS widening is seen. • Pulmonary edema • Lethargy, confusion, seizures • Metabolic: hyperglycemia, lactic acidosis, mild

hyperkalemia.

Treatment Phase I:

IV fluids

Calcium

atropine

No data to support glucagon.

Phase II:

Calcium

Pressors

Pacing

Phase III:

Intravenous Fat Emulsion

Ca Channel blocker toxitiy Pediatric PEARLS

• Seizures are more common

• Death is rare

• Refractory shock can be treated with IABP

• Verapamil IV is contraindicated for SVT in infants.

Know these two

• Nifedipine

– Single pill can kill a child

– Shortest onset

– Has Reflex tachycardia

• Verapamil

– Highest fatality rates

Nitrates/Nitrites

• Know – Nitroprusside (renal failure patients)

– PDI contraindication • Viagra et al

– Found in rural well water

– Patients with G-6PD deficiency= hemolysis

• Methemoglobinemia – Treatment methylene blue 1-2 mg IV over 5

minutes

Pesticides

• Organophosphates

– Highly lipid soluble

– Rapidly absorbed through skin

• Metabolites are ACHesterase inhibitors

Autonomic Nervous system

Muscarinic Nicotinic

Muscarinic vs. Nicotinic

• Muscarinic – Not an ion channel

– G-protein-coupled receptor

– Activate ion channels via second messenger system.

– Blocked by atropine

• Nicotinic – Ion gated channel

– Post-synaptic neuromuscular junction

– Ach causes Na entry and leads to depolorization.

– Stimulation (tremor, seizures, temp, etc)

Muscarinic Receptors • Gland excretion • Smooth muscle

relaxation

Nicotinic Receptors

• Skeletal muscle hyperstimulation

• Fasciculations

• Twitches

• Seizures

• Muscle fatigue and paralysis

• Delayed resp failure

Cholinesterase inhibitors can result in :

• Tachycardia, bradyardia

• Hypertension or hypotension

• Mydriasis, miosis

OGP Aging

• Irreversible conformational change when OGP bound to cholinesterase enzyme

• Becomes irreversible

• Varies with agent

• Importance of 2PAM

OGP Aging

• Irreversible conformational change when OGP bound to cholinesterase enzyme

• Becomes irreversible

• Varies with agent

• Importance of 2-PAM (give regardless of time from ingestion)

Diagnosis

• Clinical syndrome

• Cholinesterase levels

– RBC

– Plasma-these decrease first

• RBC cholinesterase levels correlate best with ACH activity at nerve terminal.

• RBC cholinesterase recovers slowly

Management

• 1. Decontamination

– Remove clothes, soap and water

• 2. Supportive Care

– Airway management (rocuronium better choice)

• 3. Reversal of ACH excess at muscarinic sites

• 4. reversal of toxin binding at active sites on the ACH molecule

Treatment

• Atropine 1-2 mg IV and double dose q 5 minutes until secretions dry

• Patients may need 200-300 mg

• Follow with continuous infusion:

• 5-100 mg/hr

• Pralidoxime

• Regenerates ACHesterase complex and restores ACHesterase activity at nicotinic and muscarinic sites.

• Dose: 1-2 g IV over 30 minutes repeat q 4 hours

• Benzodiazepines for seizures

Carbamates

• Differentiated from OGP by short half-life

• Reversible inhibition

• Lasts ~48 hours

• Symptoms – Twitching, hyperdynamic, rhabdo, altered MS

• Treatment – Decontamination

– Cooling measures

– Benzos

Phenols

• DNP

• Insecticides, herbicides

• Absorbed through skin

• Uncouple oxidative phosphorylation

• Hyperthermic, tachycardia, diaphoresis

• TX: early skin decon; control body temp, fluids, glucose, supportive care.

Summary

• Decon all!

• Patients die from airway compromise

• V/S and pupil findings variable

• 2-PAM should be given if you are giving atropine

• Rapid cooling and glucose the most important therapies for phenol toxicity

ACES: CV Drugs / Pesticides

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