Clinical Toxicology

Question 1

What are the two most common things people go to the ED for overdosing on?

Answer 1

Antidepressants

Benzos

Question 2

Among non-opioid analgesic overdoses, what is the most common culprit at 78%?

Answer 2

Paracetamol

Question 3

What’s the take home message about toxic pharmacokinetics?

Answer 3

We can’t compare them with therapeutic level pharmacokinetics. We need to know how they behave PK-wise at toxic levels. I.e. “ADME during overdose”.

Question 4

In what kinds of preparations have the most rapid absorption and what are the typical culprits?

Answer 4

Liquid preparations -

Paracetamol, chemicals, pesticides.

Question 5

Why would the effects of anticholinergic overdoses be delayed?

Answer 5

Reduces gut absorption, because that’s characteristic of anticolinergics.
Recall anti-cholinergic = atropine-like = sympathetic overbalance.

Question 6

What two common overdose stuffs have anticholinergic effects?

Answer 6

Antihistamines, TCAs

Question 7

Where do we need to monitor >17 hours for toxic effects?

Answer 7

Sustained release preparations.

Question 8

What’s a common sustained-release drug often overdosed on?

Answer 8

calcium-channel blockers

Question 9

Paracetamol isn’t hepatotoxic. Why do we worry about liver damage in paracetamol overdose?

Answer 9

NAPBQI binds to hepatocytes with hepatotoxic consequences. Liver damage can result.

Question 10

NAPBQI Question:

In paracetamol overdose, the K pathway experiences abnormally high flux as the W pathway and M pathways are saturated.

Answer 10

Microsomal,

Glucuronidation; Sulphation

Question 11

NAPBQI Question:
Normally the K pathway has an ample supply of R for the portion of paracetamol it metabolises. NAPBQI can rapidly conjugate to R and get pissed out. But when overworked, R is depleted and the hepatotoxic intermediate metabolise NAPBQI accumulates.

Answer 11

Microsomal; glutathione

Question 12

A Y is a tool indicate whether to treat for liver toxicity, based on Cp and hours-post-ingestion.

Answer 12

Nomogram

Question 13

A nomogram is what?

Answer 13

A graph of Cp (paracetamol) vs. hours-since-ingestion with safe zones and danger zones marked out, indicating whether or not to treat for liver toxicity.

Question 14

What pharmacokinetic quality means serum levels can rise abruptly in progressively higher doses?

Answer 14

High protein-binding.

Question 15

What is the serum-level profile for a high-Vd (typically very lipophilic) drug?

Answer 15

[early toxicity because of a] rapid increase upon entry into the bloodstream, with progressive reduction due to redistribution.

Question 16

What is the significance of a high Vd drug in terms of management strategy and why?

E.g. someone’s in cardiac arrest because they’ve overdosed on TCAs. What do you know you have in store?

Answer 16

EARLY TOXICITY because of rapid entry to the bloodstream, but that THE GAME’S NOT OVER once it’s under control, since we’re still wary of the toxicant reentering the blood compartment.

Re TCA overdose: We’re gonna be resuscitating for cardiac arrest, but we’re gonna be at it for a while because the causative agent is gonna keep leeching from the body back into the blood keeping cardiac conduction fucked.

Question 17

Apart from protein binding, what can knock serum levels up abruptly in overdose? What’s a typical example?

Answer 17

Hepatic metabolism can get saturated, knocking 1st order kinetics to zero-order kinetics.

Example: aspirin (Pka 3.0), renal clearance only mechanism during OD.

Question 18

Pharmacodynamics question:

What’s an important example of receptor-density modification and what’s the danger?

Answer 18

Opioids. Famously they induce physical tolerance by increasing receptor endocytosis and degradation.

Overdose wise - big problems occur AFTER WITHDRAWAL, during which receptor density has recuperated, when the user takes an identical dose.

Question 19

Apart from receptor-density changes, what is a major pharmacodynamic concept?

Answer 19

Loss of specificity.

Question 20

As a cross-over with antidepressants, relate TCA overdose symptoms to four losses of specificity.

Answer 20

ALPHA2 BLOCKADE - hypotension (vasodilation)
NA(v) BLOCKADE - disrupted conduction problems
mAChR BLCOKADE - ANTICHOLINERGIC
GABA2 BLOCKADE - lowered seizure threshold

Question 21

Toxicodynamics question:

List the four blockades that occur with decreased TCA specificity during overdose?

Answer 21

Alpha2,
GABA2,
mAChR, p
Na(V)

Question 22

Most ODs are very undifferentiated upon presentation. What are the practical steps to take when someone admits with an overdose?

Answer 22

ABC - airway, breathing, circulation; check O2 sat.
Check for hypoglycaemia.
Do a toxicology screen.

OD deaths are uncommon.

Question 23

What are the three pharmacological steps in responding to an OD?

Answer 23

Hinder absorption
Help elimination
Give antidote where possible.

Question 24

How long after ingestion is it too late for charcoal therapy?

Answer 24

1-2 hours. It really only helps with [non-polar] stuff that’s STILL in the GI tract.

Question 25

Doctor! This bipolar guy has overdosed on his lithium! When should I administer the charcoal?

Answer 25

Never. Charcoal’s good for non-polar solutes only, and not heavy metals (or hydrocarbons, or alcohol, or corrosives).

Question 26

It’s the night of November 8th 2016, Trump’s just been elected.
One patient has injested draino, another the other petrol, another on antifreeze. BUT, there’s only one dose of activated charcoal left because the healthcare system is so fucked. Which patient do you give the charcoal to?

Answer 26

Trick question. You keep it for when someone overdoses on something that charcoal can actually absorb.

Bonus: give the antifreeze guy ethanol - preferred substrate, gives you time to haemodialyse the antifreeze out.

Question 27

What’s the alternative to charcoal when charcoal won’t work/won’t work?

Answer 27

Polyethylene glycol. Flushes out. So it’s also way better for heavy metals (and body stuffers).

Question 28

What two absorption-preventing responses are no longer routinely used?

Answer 28

1. gastric lavage (too dangerous for the low effectiveness)

2. epicac (poor if any gastric emptying).

Question 29

What are the three appraoches to enhanced elimination?

Answer 29

MDAC (low evidence)
Urinary alkalisation
Haemodyalisis (limited)

Question 30

What’s the idea behind multiple dose activated charcoal? (MDAC)

Answer 30

Lowered concentration via enhanced diffusion back into the GI tract. Not very effective.

Question 31

Is urinary alkalisation good for low Pka drugs or high Pka drugs?

Answer 31

Low (e.g. aspirin and other salycilates).

Lower pka = more acidic

Question 32

What’s the rationale behind urinary alkalisation for enhanced clearance?

Answer 32

If the toxicant is a weak acid (low Pka e.g. aspirin) we can enhance the proportion of charged species, lowering reabsorption, thereby reducing half-life.

Question 33

What’s the THM for antidotes?

Answer 33

Only a handful are available and there are risks to weigh in light of iffy efficacy.

Question 34

What are the arguments for risk with antidotes?

Answer 34

May not change the outcome,

May have their own toxic effects.

Question 35

What’s that common phenomenon with opioid overdose patients that doctors deal with and what does it reflect about the naloxone antidote for opioid overdose?

Answer 35

Addicts would perk up when the effects of naloxone kicked in, and promptly vamoose. But that makes the doctor fret because naloxone has a SHORT HALF LIFE meaning that resedation is possible once the antidote is cleared.

Question 36

What is the mechanism of naloxone?

Answer 36

It’s a high affinity µ-receptor antagonist.

Bonus: It might induce withdrawal but withdrawal isn’t life threatening. Certainly not when you’re already receiving medical attention.

Question 37

What’s the mechanistic basis of ethanol as an antidote to X?

Answer 37

As an antidote to antifreeze (ethylene glycol) or methanol. Since the toxic basis of these is their toxic metabolites + they share the alcohol dehydrogenase as an enzyme, you can use alcohol as the PREFERRED SUBSTRATE, which will buy you time for HAEMODIALYSIS.

Question 38

What antidote is sort of like an antivenom and why?

Answer 38

Digibind (against digoxin) is made from anti-digoxin antibodies like antivenoms are. It’s great apparently.

Bonus: one thing doctors like about it is that it can mop up more than a geriatric can ever double up on by mistake.