Running head: From Pharmacological Mechanisms to Precision Medicine (BBS3012) 1
From Pharmacological Mechanisms to
Precision Medicine (BBS3012)
Case 1, 2, 3
Name
Institution
Course
Tutor
Date
,From Pharmacological Mechanisms to Precision Medicine (BBS3012) 2
CASE 1
DOSE AND DOSING INTERVAL DETERMINE
THERAPEUTIC AND TOXIC EFFECTS OF A
BIOLOGICALLY ACTIVE COMPOUNDS
PS: Pharmacokinetics (look at ADME in general and apply it to alcohol and
paracetamol)
BS: Peter swallowed 26 paracetamol tablets (500 mg x 26 = 13 000 mg or 13 g) 13
000/mg divided by 70 kg BW = 185 mg/kg – severe liver damage follows.
LG:
1. What is the ADME of alcohol?
→ Absorption:
Absorption is quick and almost complete after oral intake. Absorption occurs via GI
system, primarily in the duodenum and the remainder in the small intestine (approx.
80%) and stomach (20%). When the stomach is empty, peak blood ethanol levels are
reached between 30 and 90 minutes after ingestion. Food and particularly carbohydrates
retards absorption: blood concentration may not reach a quarter of those achieved on
empty stomach. Absorption also takes place through the skin and by inhalation.
Absorption occurs by passive diffusion, down its concentration gradient.
→ Distribution:
Alcohol molecule is a small polar molecule with lipophilic and hydrophilic
characteristics.
Vd 0.5-0.7 L / kg, alcohol is completely soluble in water and thus has a similar volume
of distribution to total body water.
,From Pharmacological Mechanisms to Precision Medicine (BBS3012) 3
Protein binding has not been reported.
→ Metabolism:
More than 90% of alcohol is eliminated by the liver, 2-5% is excreted unchanged in
urine, sweat or breath.
First step is oxidation by alcohol dehydrogenase to acetaldehyde. Oxidation of alcohol
by gastric ADH accounts for small proportion of first pass metabolism, but the majority
occurs via oxidation by ADH in the liver hepatocytes. Acetaldehyde is highly reactive
and toxic substance and in healthy people it is oxidized rapidly by aldehyde
dehydrogenases to acetate.
Secondary oxidation pathway for alcohol metabolism is the microsomal alcohol
oxidizing system involving microsomal cytochrome (P450) – CYP2E1 which accounts
for about 10% of total alcohol clearance by liver at low concentrations. Enzyme
CYP2E1 produces ROS – acetaldehyde and 1hydroxyethyl radical.
Metabolism is mostly enzyme catalyzed and thus Michaelis Menten kinetics (enzyme
kinetics) apply. Reaction rate can reach a certain maximum speed (Vmax) if the
substrate concentrations are too high – enzymes will be saturated.
→ Excretion:
Alcohol is removed from the blood at a rate about 3.3 mmol/hour (15 mg/100ml/hour)
but varies.
2.5% of unchanged alcohol is excreted in urine.
Alcohol follows zero-order kinetics because the elimination does not depend on the
concentration.
, From Pharmacological Mechanisms to Precision Medicine (BBS3012) 4
7g/h is for 1 glass/h for an average person.
1 drink has average 15 g alcohol.
15 g/42 = 0.3 g/L meaning it is highly concentrated.
2. What are the effects of alcohol on the body? (quantitative way – at such a
concentration of alcohol this will happen etc.)
Ethanol is used as a stimulant and has a higher dose inhibitory effect on the central
nervous system and motor functions.
→ Alcohol intoxication
Toxic effects are expected from intake of 600 mg / kg or a blood level of 1000 mg / L.
The following are mentioned as life-threatening concentrations:
> 5000 mg / L (shortly after ingestion) or > 4000 mg / L (.5 hours after ingestion) resp.
as lifethreatening doses of 5-8 g / kg for adults; 3 g / kg for children. However, these are
only guide values; there are large inter-individual differences.
N.B .: 1 promile = 1000 mg / L
→ Therapeutic value
N/A
→ Toxic value
100 mg/dl or 22 mmol/L: euphoria, mild deficits in coordination, attention and cognition
1000 - 1500 mg / L: reduced motor function, balance, coordination
1500 - 2500 mg / L: lethargy
3000 mg / L: stupor (lack of critical metal function and level of consciousness)
4000 - 5000 mg / L: coma, respiratory depression, hypothermia, potential lethal
From Pharmacological Mechanisms to
Precision Medicine (BBS3012)
Case 1, 2, 3
Name
Institution
Course
Tutor
Date
,From Pharmacological Mechanisms to Precision Medicine (BBS3012) 2
CASE 1
DOSE AND DOSING INTERVAL DETERMINE
THERAPEUTIC AND TOXIC EFFECTS OF A
BIOLOGICALLY ACTIVE COMPOUNDS
PS: Pharmacokinetics (look at ADME in general and apply it to alcohol and
paracetamol)
BS: Peter swallowed 26 paracetamol tablets (500 mg x 26 = 13 000 mg or 13 g) 13
000/mg divided by 70 kg BW = 185 mg/kg – severe liver damage follows.
LG:
1. What is the ADME of alcohol?
→ Absorption:
Absorption is quick and almost complete after oral intake. Absorption occurs via GI
system, primarily in the duodenum and the remainder in the small intestine (approx.
80%) and stomach (20%). When the stomach is empty, peak blood ethanol levels are
reached between 30 and 90 minutes after ingestion. Food and particularly carbohydrates
retards absorption: blood concentration may not reach a quarter of those achieved on
empty stomach. Absorption also takes place through the skin and by inhalation.
Absorption occurs by passive diffusion, down its concentration gradient.
→ Distribution:
Alcohol molecule is a small polar molecule with lipophilic and hydrophilic
characteristics.
Vd 0.5-0.7 L / kg, alcohol is completely soluble in water and thus has a similar volume
of distribution to total body water.
,From Pharmacological Mechanisms to Precision Medicine (BBS3012) 3
Protein binding has not been reported.
→ Metabolism:
More than 90% of alcohol is eliminated by the liver, 2-5% is excreted unchanged in
urine, sweat or breath.
First step is oxidation by alcohol dehydrogenase to acetaldehyde. Oxidation of alcohol
by gastric ADH accounts for small proportion of first pass metabolism, but the majority
occurs via oxidation by ADH in the liver hepatocytes. Acetaldehyde is highly reactive
and toxic substance and in healthy people it is oxidized rapidly by aldehyde
dehydrogenases to acetate.
Secondary oxidation pathway for alcohol metabolism is the microsomal alcohol
oxidizing system involving microsomal cytochrome (P450) – CYP2E1 which accounts
for about 10% of total alcohol clearance by liver at low concentrations. Enzyme
CYP2E1 produces ROS – acetaldehyde and 1hydroxyethyl radical.
Metabolism is mostly enzyme catalyzed and thus Michaelis Menten kinetics (enzyme
kinetics) apply. Reaction rate can reach a certain maximum speed (Vmax) if the
substrate concentrations are too high – enzymes will be saturated.
→ Excretion:
Alcohol is removed from the blood at a rate about 3.3 mmol/hour (15 mg/100ml/hour)
but varies.
2.5% of unchanged alcohol is excreted in urine.
Alcohol follows zero-order kinetics because the elimination does not depend on the
concentration.
, From Pharmacological Mechanisms to Precision Medicine (BBS3012) 4
7g/h is for 1 glass/h for an average person.
1 drink has average 15 g alcohol.
15 g/42 = 0.3 g/L meaning it is highly concentrated.
2. What are the effects of alcohol on the body? (quantitative way – at such a
concentration of alcohol this will happen etc.)
Ethanol is used as a stimulant and has a higher dose inhibitory effect on the central
nervous system and motor functions.
→ Alcohol intoxication
Toxic effects are expected from intake of 600 mg / kg or a blood level of 1000 mg / L.
The following are mentioned as life-threatening concentrations:
> 5000 mg / L (shortly after ingestion) or > 4000 mg / L (.5 hours after ingestion) resp.
as lifethreatening doses of 5-8 g / kg for adults; 3 g / kg for children. However, these are
only guide values; there are large inter-individual differences.
N.B .: 1 promile = 1000 mg / L
→ Therapeutic value
N/A
→ Toxic value
100 mg/dl or 22 mmol/L: euphoria, mild deficits in coordination, attention and cognition
1000 - 1500 mg / L: reduced motor function, balance, coordination
1500 - 2500 mg / L: lethargy
3000 mg / L: stupor (lack of critical metal function and level of consciousness)
4000 - 5000 mg / L: coma, respiratory depression, hypothermia, potential lethal
