Clinical toxicology
Lecture 1 Introduction
Children eats cherrylaurel contains cyanide toxic. Instead, make the cyanide leaf water
from the pharmacopeia. Here 1 kg of leaf is distilled, forming about 1 g of HCN. 1 leaf weighs
about 1 gram. Is this toxic? 0,1 g hydrocyanic acid is acute lethal. So the boy could eat 100
leafs before it would be toxic.
Enzymes in our saliva are able to split of the cyanide. So when chewing cherry laurel you are
liberating cyanide. Also, the plant itself can form cyanides to protect itself from being eaten.
Poisons can come from plants, animals, minerals, etc. One famous poison is curare in the
milk of the plant. In here, there is D-tubocurarine, which is a muscle relaxant by interfering
with the cholinergic receptors. It is only active when parenterally administered, so it is used
as paralysis in both a poisonous way (for animals) or clinically during surgical operations.
Hemlock nicotine agonist which can stimulate the cholinergic system, you can paralyse
due to exhaustion of the cholinergic system. There is permanent stimulation of the
postsynaptic cholinergic receptors, so permanent depolarization and convulsions. So the
muscles are continuously stressed leading to paralysis.
Other poisonous plants:
- Aconitum (persistent activation of sodium channels in the heart leading to tachy-
arrhythmias)
- Hyosciamus
- Mandragora (podophyllotoxin causing delirium, hallucinations, nausea, vomiting,
abdominal pain, neurotoxicity, hematologic toxicity)
- Papaver (morphine/codeine/papaverine leading to signs and symptoms of opiate
intoxication, sedation and respiratory depression).
Poisonous animals: toads, salamander (tetrodotoxin), fish (tetrodotoxin), snakes, shellfish
(saxitoxin).
All substances are poisons, only the dose makes the difference. A poison is a substance that
causes disturbances to organisms usually by chemical reaction or other activity on a
molecular scale, when a sufficient quantity is absorbed
Mineral poisons:
- Arsenic (As3+, As5+)
- Lead (Pb2+)
- Antimony (Sb3+, Sb5+)
- Mercury (Hg+, Hg2+)
Gaseous poisons:
- Carbon monoxide (CO)
- Hydrogen sulfide (H2S)
- Ammonia (NH3)
Poisoning can be intentional (murder, suicide) or accidental (organ dysfunction, drug-drug
interactions, medical error, accident). A poisoning is totally different from a side effect. A side
effect is unwanted but at a normal dose. A poisoning is when the dose is too high.
Burghwal water can be used to detect ionised heavy metals as it contains H2S.
Marsh test was used to detect arsenic in the body.
,Chromatography separates compounds over a column.
UV spectrophotometry/diode-array detection is highly specific, but not sensitive enough. So
nowadays we use mass spectrometry.
Know the difference between MS and MSMS. Single MS is measuring a compound with a
certain mass, but many molecular structures have the same mass. To know for sure which
drug you are dealing with, we are using tandem mass spectrometry. So in the first MS you
select the mass of your drug of interest. Then the drug is fragmented with an ion beam and
then you look at the daughter compounds of the drug that are formed after collision with the
ion beam. This method is highly specific and highly sensitive.
Differences toxicology – medicine:
- No randomised controlled trials
- Usually case reports, sometimes case series
- Little information about its toxicity during introduction of a new drug (only animal)
- Little information about treatment of an intoxication during introduction of a new drug
- Knowledge of caregivers about intoxications is limited
- Toxicology is a multidisciplinary approach
- There is little funding for toxicological research on drugs (companies will not be
associated with toxicity of their drugs)
Detection of toxic substances is a challenge. Modern analytical techniques are capable to
detect poisons in the sub microg/L range.
Pharmacokinetics and toxicokinetics
Case: patient took 50 digoxin tablets of 0,25 mg. There were no symptoms of toxicity. please
measure the digoxin concentration to verify the story. It came out: digoxin is 22 microg/L. the
therapeutic window is 0.8-2.2 microg/L and >4 microg/L is toxic. So this concentration is
extremely toxic. Now symptoms did occur and later the patient has died. The processes in
the body lagged behind because it takes time for the compound to reach the site of action.
This can be due to slow distribution towards the cardiac tissue (target site).
Case: patient was treated with lithium, but this dose was too large for her renal function. This
leads to chronic intoxication. She had severe toxicity symptoms and too high lithium
concentrations. She was dialysed and treated with supportive care, the concentrations
dropped to therapeutic. But still toxicity symptoms were there for a few weeks. So even after
the lithium is already out of the body, the symptoms still are there. This is due to a slow
,redistribution of lithium from the CNS to other tissue. So during dialysis the lithium in the
brain is not cleared and it will stay there for a while.
All drug goes from the gut to the liver so is very vulnerable to toxic effects. Also the kidney is
vulnerable as it is also exposed to relatively high concentrations due to the excretion
process.
First phase = distribution phase first phase intersect is the initial dilution volume, so V in
the central compartment.
Second phase = elimination phase second phase extrapolation intersect is the total
volume of distribution.
The second compartment gives a better estimation of the effect, but we cannot measure in
the peripheral, only in the central. We can only model what happens in the peripheral
compartment and link this to the effect. But we cannot measure where we want to measure.
Example:
t=5 C=125 mg/L
BW = 70 kg, t1/2 of paracetamol = 3h
Cmax = F*amount ingested/V
C(t) = Cmax * e-kt
k = ln2/t1/2 = ln = 0.231 h-1
F = 1, V = 0.88 L/kg = 70*0.88 =
, C(5) = 125 = Cmax*e-0.231*5 Cmax = … mg/L
Amount ingested = Cmax*V =
It is relevant to know to which concentration the toxic effect is related: concentration in the
central compartment or concentration in a peripheral compartment: cardiac, CNS, skin, other.
The therapeutic range is usually based on measurement in blood. The therapeutic range is
where 50% of the patients responds (lower limit), until where 10% observes toxicity (upper
limit). It are sigmoidal curves and not everyone will fit into this model.
PK is first preclinically investigated in animals. Then in healthy volunteers (phase I), then
during phase II and III patients are involved. And you cannot investigate intentional
overdoses. So you have to rely on the case reports of intoxications as you do not test on this.
Types of intoxications with drugs:
- Overdose
- Reduction of clearance
- Increased bioavailability
Absorption: Drug disintegration, Absorption rate, Bioavailability
Distribution: Protein binding, Rate, Volume
Metabolism: Hepatic, Other
Elimination: Renal, Bile, Other
Overdose can lead to slow disintegration so it can take days for all tablets to be disintegrated
and dissolved. So the absorption rate is extremely slow compared to one tablet. This can
also mean that bioavailability is less. Retard tablets tend to have a more sticky mass than
conventional tablets. The absorption rate can also be slower due to anticholinergic properties
of the drug as there are slower gut movements leading to lower absorption. Also
bioavailability can be increased in overdosing due to saturation of the pGP efflux pump which
is located in the gut wall. So the export system gets saturated, so much more drug is
absorbed and also the gut metabolism can get saturated meaning that there is more intact
drug which will be absorbed. Bioavailability can also be increased, due to an increased GI
transit time due to the anticholinergic properties of a drug. F can also increase due to
saturation of first pass metabolism in the liver and saturation of CYP enzymes. These
methods all account for overdose and drug-drug interactions. Be aware of the formation of
active metabolites.
Drug distribution: drug needs to be transported to peripheral tissues via the bloodstream.
This can be protein bound or free. Only free drug can distribute. The rate of distribution is
usually not affected by the concentration, as well as V. However, protein binding is affected
as it can get saturated in case of an overdose. Protein binding can be affected by pH. So the
Lecture 1 Introduction
Children eats cherrylaurel contains cyanide toxic. Instead, make the cyanide leaf water
from the pharmacopeia. Here 1 kg of leaf is distilled, forming about 1 g of HCN. 1 leaf weighs
about 1 gram. Is this toxic? 0,1 g hydrocyanic acid is acute lethal. So the boy could eat 100
leafs before it would be toxic.
Enzymes in our saliva are able to split of the cyanide. So when chewing cherry laurel you are
liberating cyanide. Also, the plant itself can form cyanides to protect itself from being eaten.
Poisons can come from plants, animals, minerals, etc. One famous poison is curare in the
milk of the plant. In here, there is D-tubocurarine, which is a muscle relaxant by interfering
with the cholinergic receptors. It is only active when parenterally administered, so it is used
as paralysis in both a poisonous way (for animals) or clinically during surgical operations.
Hemlock nicotine agonist which can stimulate the cholinergic system, you can paralyse
due to exhaustion of the cholinergic system. There is permanent stimulation of the
postsynaptic cholinergic receptors, so permanent depolarization and convulsions. So the
muscles are continuously stressed leading to paralysis.
Other poisonous plants:
- Aconitum (persistent activation of sodium channels in the heart leading to tachy-
arrhythmias)
- Hyosciamus
- Mandragora (podophyllotoxin causing delirium, hallucinations, nausea, vomiting,
abdominal pain, neurotoxicity, hematologic toxicity)
- Papaver (morphine/codeine/papaverine leading to signs and symptoms of opiate
intoxication, sedation and respiratory depression).
Poisonous animals: toads, salamander (tetrodotoxin), fish (tetrodotoxin), snakes, shellfish
(saxitoxin).
All substances are poisons, only the dose makes the difference. A poison is a substance that
causes disturbances to organisms usually by chemical reaction or other activity on a
molecular scale, when a sufficient quantity is absorbed
Mineral poisons:
- Arsenic (As3+, As5+)
- Lead (Pb2+)
- Antimony (Sb3+, Sb5+)
- Mercury (Hg+, Hg2+)
Gaseous poisons:
- Carbon monoxide (CO)
- Hydrogen sulfide (H2S)
- Ammonia (NH3)
Poisoning can be intentional (murder, suicide) or accidental (organ dysfunction, drug-drug
interactions, medical error, accident). A poisoning is totally different from a side effect. A side
effect is unwanted but at a normal dose. A poisoning is when the dose is too high.
Burghwal water can be used to detect ionised heavy metals as it contains H2S.
Marsh test was used to detect arsenic in the body.
,Chromatography separates compounds over a column.
UV spectrophotometry/diode-array detection is highly specific, but not sensitive enough. So
nowadays we use mass spectrometry.
Know the difference between MS and MSMS. Single MS is measuring a compound with a
certain mass, but many molecular structures have the same mass. To know for sure which
drug you are dealing with, we are using tandem mass spectrometry. So in the first MS you
select the mass of your drug of interest. Then the drug is fragmented with an ion beam and
then you look at the daughter compounds of the drug that are formed after collision with the
ion beam. This method is highly specific and highly sensitive.
Differences toxicology – medicine:
- No randomised controlled trials
- Usually case reports, sometimes case series
- Little information about its toxicity during introduction of a new drug (only animal)
- Little information about treatment of an intoxication during introduction of a new drug
- Knowledge of caregivers about intoxications is limited
- Toxicology is a multidisciplinary approach
- There is little funding for toxicological research on drugs (companies will not be
associated with toxicity of their drugs)
Detection of toxic substances is a challenge. Modern analytical techniques are capable to
detect poisons in the sub microg/L range.
Pharmacokinetics and toxicokinetics
Case: patient took 50 digoxin tablets of 0,25 mg. There were no symptoms of toxicity. please
measure the digoxin concentration to verify the story. It came out: digoxin is 22 microg/L. the
therapeutic window is 0.8-2.2 microg/L and >4 microg/L is toxic. So this concentration is
extremely toxic. Now symptoms did occur and later the patient has died. The processes in
the body lagged behind because it takes time for the compound to reach the site of action.
This can be due to slow distribution towards the cardiac tissue (target site).
Case: patient was treated with lithium, but this dose was too large for her renal function. This
leads to chronic intoxication. She had severe toxicity symptoms and too high lithium
concentrations. She was dialysed and treated with supportive care, the concentrations
dropped to therapeutic. But still toxicity symptoms were there for a few weeks. So even after
the lithium is already out of the body, the symptoms still are there. This is due to a slow
,redistribution of lithium from the CNS to other tissue. So during dialysis the lithium in the
brain is not cleared and it will stay there for a while.
All drug goes from the gut to the liver so is very vulnerable to toxic effects. Also the kidney is
vulnerable as it is also exposed to relatively high concentrations due to the excretion
process.
First phase = distribution phase first phase intersect is the initial dilution volume, so V in
the central compartment.
Second phase = elimination phase second phase extrapolation intersect is the total
volume of distribution.
The second compartment gives a better estimation of the effect, but we cannot measure in
the peripheral, only in the central. We can only model what happens in the peripheral
compartment and link this to the effect. But we cannot measure where we want to measure.
Example:
t=5 C=125 mg/L
BW = 70 kg, t1/2 of paracetamol = 3h
Cmax = F*amount ingested/V
C(t) = Cmax * e-kt
k = ln2/t1/2 = ln = 0.231 h-1
F = 1, V = 0.88 L/kg = 70*0.88 =
, C(5) = 125 = Cmax*e-0.231*5 Cmax = … mg/L
Amount ingested = Cmax*V =
It is relevant to know to which concentration the toxic effect is related: concentration in the
central compartment or concentration in a peripheral compartment: cardiac, CNS, skin, other.
The therapeutic range is usually based on measurement in blood. The therapeutic range is
where 50% of the patients responds (lower limit), until where 10% observes toxicity (upper
limit). It are sigmoidal curves and not everyone will fit into this model.
PK is first preclinically investigated in animals. Then in healthy volunteers (phase I), then
during phase II and III patients are involved. And you cannot investigate intentional
overdoses. So you have to rely on the case reports of intoxications as you do not test on this.
Types of intoxications with drugs:
- Overdose
- Reduction of clearance
- Increased bioavailability
Absorption: Drug disintegration, Absorption rate, Bioavailability
Distribution: Protein binding, Rate, Volume
Metabolism: Hepatic, Other
Elimination: Renal, Bile, Other
Overdose can lead to slow disintegration so it can take days for all tablets to be disintegrated
and dissolved. So the absorption rate is extremely slow compared to one tablet. This can
also mean that bioavailability is less. Retard tablets tend to have a more sticky mass than
conventional tablets. The absorption rate can also be slower due to anticholinergic properties
of the drug as there are slower gut movements leading to lower absorption. Also
bioavailability can be increased in overdosing due to saturation of the pGP efflux pump which
is located in the gut wall. So the export system gets saturated, so much more drug is
absorbed and also the gut metabolism can get saturated meaning that there is more intact
drug which will be absorbed. Bioavailability can also be increased, due to an increased GI
transit time due to the anticholinergic properties of a drug. F can also increase due to
saturation of first pass metabolism in the liver and saturation of CYP enzymes. These
methods all account for overdose and drug-drug interactions. Be aware of the formation of
active metabolites.
Drug distribution: drug needs to be transported to peripheral tissues via the bloodstream.
This can be protein bound or free. Only free drug can distribute. The rate of distribution is
usually not affected by the concentration, as well as V. However, protein binding is affected
as it can get saturated in case of an overdose. Protein binding can be affected by pH. So the
