Drug Induced Hypotension & Bradycardia

What is the formula for cardiac output?

CO = HR x SV

Define heart rate (HR)

Beats per minute

Define stroke volume (SV)

mL per beat

What drug classes can cause drug-induced bradycardia?

Beta-blockers

Calcium channel blockers

Digoxin

a2 agonists

What two beta-blockers can cause drug-induced bradycardia?

Propranolol and sotalol

What are the toxic effects of propranolol?

Wide QRS (due to membrane stabilizing ability)

Seizures

Multiple system atrophy (MSA)

What are the toxic effects of sotalol?

Prolong QTc

hERG blockage

What can beta-blockers cause in pediatric patients?

Hypoglycemia

What are the toxic effects of non-DHP CCBs?

Bradycardia/hypotension

What are the toxic effects of DHP CCBs?

Hypotension + reflex tachycardia

What are the toxic effects of digoxin?

Increased inotropy at therapeutic levels

Decreased chronotropy and increased automaticity at toxic levels

Which a2 agonists can cause drug-induced bradycardia?

Clonidine/guanfacine

Oxymetazoline/tetrahydrozoline

Dexmedetomidate

Tizanidine

Define Fick's principle

Decreased CO2 = decreased O2 delivery

What drug classes decrease SVR?

CCBs

a2 agonists

How do CCBs decrease SVR?

non-DHP = cardiac, also cause bradycardia

DHP = only SVR, also cause tachycardia

How do a2 agonists decrease SVR?

Decrease stimulatory NTs

Decrease NTs by binding presynaptic a2 receptor

What is the primary site where epi/NE can bind to increase HR?

Beta 1 receptors located on the heart

Describe how HR increases following the binding of NTs to beta 1 receptors

G protein leaves GPCR and activates adenylyl cyclase = increases cAMP

cAMP activates PKA to activate calcium influx from L-type calcium channels, triggering reuptake into sarcoplasmic reticulum

Calcium is released from the SR, leading to increased HR and sqeeze

What happens when beta 1 receptors are blocked due to drugs?

NTs cannot bind to beta 1 receptors = no downstream effects

Leads to decreased calcium influx, HR, BP, etc.

What drugs are non-DHP CCBs?

Diltiazem

Verapamil

What toxic effects can non-DHP CCBs have?

Hypotension / Bradycardia

What drugs are DHP CCBs?

Amlodipine

Clevidipine

Nicardipine

Nifedipine

Nimodipine

What toxic effects can DHP CCBs have?

Hypotension / Tachycardia

NO bradycardia since these drugs do not effect the heart, instead cause reflex tachycardia

How do CCBs affect the heart?

Bind to and inhibit L-type calcium channels

Inhibit calcium entry into the cell = less squeeze and rate of the heart

How do CCBs affect the vessels?

Mechanism is the same as in the heart

L-type calcium channels in the vessels are responsible for calcium influx into the vessels leading to calcium release in the vessels

Causes smooth muscle constriction = increase in squeeze, BP, and SVR

What can an overdose of a CCB cause?

Decreased insulin release

Once there is an overdose of CCBs, they will also block L-type calcium channels in the pancreas which are responsible for releasing insulin

Can lead to hyperglycemia

Describe GI decontamination in drug-induced hypotension and bradycardia

Decreases drug absorption

High utility here because of the prolonged window of benefit

What increases the window of benefit for activated charcoal in drug-induced hypotension and bradycardia?

Delayed release preparations

Slows GI motility (common with CCB overdose)

What are the limitations of using GI decontamination in drug-induced hypotension and bradycardia?

CNS depression/altered mental status

Hypotension = decreases GI motility meaning that MDAC cannot be used

What are the initial therapies for drug-induced hypotension and bradycardia?

Atropine

Glucagon

Calcium

Describe atropine as an initial therapy

Improved HR by blocking ACh

Increases HR = increases CO

Used for any patient with symptomatic bradycardia = not specific for drug-induced hypotension and bradycardia

Describe glucagon as an initial therapy

ANTIDOTE for beta-blocker toxicity

AE = N/V

IV dose with a short duration of action

Describe calcium as initial therapy

ANTIDOTE for CCBs

Calcium chloride or calcium gluconate

What are the routes of administration for calcium chloride vs. calcium gluconate?

Chloride = central line due to vessel irritation

Gluconate = peripheral line

What are the two mechanisms through which antidotes work for drug-induced hypotension and bradycardia?

Second "on-switch" the heart has = glucagon receptor

L-type calcium channel is blocked by a CCB = can overcome it with calcium

Describe vasopressor treatment

Used for patients who have failed supportive measures

Use DIRECT acting vasopressors = NE and epinephrine

Titrate to stable HR and MAP > 65 mmHg

What are adverse effects of direct acting vasopressors?

Ischemia, tachydysrhythmias

Increase duration/number of vasopressors = increased AEs

What is the mechanism of high-dose insulin?

Increases glucose uptake/utilization

Inotrope = increases SV

Used for non-DHP CCBs + beta-blockers

What are adverse effects of high-dose insulin?

Hypoglycemia = use dextrose to maintain glucose > 100 mg/dL

Hypokalemia = supplement to goal of 3.5-4 mmol/L

When should patients get a bolus dose of glucose before an infusion?

BG ≤ 250 mg/dL

What should a glucose infusion be titrated to maintain?

BG > 100 mg/dL

What is the target goal for potassium?

4 mEq/L

Reassess frequently

What are additional therapies for when first and second line therapies are not working?

Methylene blue

Angiotensin II

ECMO

What are the initial treatments to increase heart rate in drug-induced bradycardia?

Atropine / glucagon

What is the initial treatment to increase squeeze in drug-induced hypotension and bradycardia?

Calcium

What are the next steps in treating drug-induced hypotension and bradycardia?

Vasopressors = increase HR/BP

HIET = inotrope (increases squeeze)

What should be monitored when treating drug-induced hypotension and bradycardia?

MAP > 65 mmHg

Lactate

Mental status / end organ

ECHO

Describe a2 agonist activity

Bind presynaptic a2 receptors = decreases epi/NE release

Causes decreases in HR/BP, CNS/respiratory depression

Causes miosis

Looks very similar to an opioid toxidrome, main difference is vital signs

What are the treatments for a2 agonist toxicity?

IV fluids, atropine

High-dose naloxone

Vasopressors

Endotrachial intubation

Describe how high-dose naloxone is used to treat a2 agonist toxicity

Clonidine causes beta-endorphin release that contributes to decreased HR/BP

Naloxone reverses this