Zusammenfassung
Summary of all colleges Metabolism and Toxicology
- Kurs
- Hochschule
Summary of all lecture notes Metabolism and Toxicology
[ Mehr anzeigen ]vorschau 4 aus 97 Seiten
Vorschau 4 aus 97 Seiten
In den Einkaufswagen
In den Einkaufswagen
Verkäufer
Folgeneliselammers
Deine Reviews
Inhaltsvorschau
Metabolism and ToxicologyIntroduction
Metabolism: chemical transformations that compounds undergo in the body
= what does the body do to a compound
Toxicology: adverse effects of chemicals on organisms
= what does the compound do to the body
Paracetamol → safe painkiller (max 6 a day; 3 gram)
Deadly dose: approximate 30 gram
• Works after 30 minutes → needs to be absorbed
• Stops working after 6 hours → its metabolized then
Water-soluble compound is inefficiently absorbed and easily excreted.
Most drugs are lipophilic → to enter cells compounds need to pass membranes
• When compound reaches the bloodstream → bound to albumin (big protein)
• Clearance is slow → lipophilic drugs cannot be excreted
Compounds need to become hydrophilic (water-soluble) to can be excreted.
• Metabolism transforms a lipophilic compound into a water-soluble compound that can be
excreted
Lipophilic drugs → backbone conjugated with polar molecules → easily excreted
Toxification
Cytochrome P450 → hydroxylation on nitrogen atom of paracetamol
• Unstable intermediate
→ transforms into NAPQ: responsible for toxic reactions in the body (electrophilic + load)
→ bind easily to nucleophiles → cell damage
Dose
Once: >70 mg/kg, toxic effects 5 gram
>140mg/kg, moderate liver damage 10 gram
>200mg/kg, severe liver damage 14 gram
Chronic use: 3-4 g/day: liver damage
Toxicity enhanced by chronic alcohol use and by certain drugs such as carbamazepine, isoniazid and
barbiturates.
Antidote: N-acetylcysteine or methionine
Toxification or bioactivation → metabolites are more toxic than parent compound
Detoxification → metabolites less toxic than parent compound
ADR → adverse drug reaction
Off label use → toxic effect may sometimes be a desirable effect for other diseases
Adverse effect: any (unwanted) effect of a drug that interferes with the normal function and
adaptability of the body to (stimuli from) the environment.
,Targets of toxicity
• Receptors
• Other proteins: enzymes, transporters etc.
• Membrane-lipids
• DNA/RNA
• Ca2+ homeostasis
• Ion channels
• Mitochondria (energy)
Manifestations of toxic effects
• Local → systemic
• Rapid onset/acute → delayed/chronic
• Reversible → irreversible
• Gradual → all or nothing
• Direct → indirect
Adverse effects
• Cell death
• Pharmacological/physiological effects
• Genotoxicity
• Carcinogenicity
• Reproduction damage
• Teratogenicity
• Neurotoxicity
• Immunotoxicity, sensitization,
• Irritation (skin, eye)
Toxic effects by the immune system: immunological response to damage somewhere in the body,
e.g. sensitization, hapten formation
On-target toxicity: undesirable effect due to exaggerated pharmacological effect
› For example, by increased exposure of the target (higher blood concentrations, etc.),
interaction with the same target on/in another cell/organ
Off-target toxicity: undesirable effect via a completely different mechanism (different target) than
pharmacological effect
› dose response curve of the toxic effect ≠ intended pharmacological effect
,Dose-response curve
• Responders and no responders
• Y-axis: cumulative response %
• TD50
Hormesis: effect between dose and effect is U-shaped
E.g. effect vitamin A on embryo development.
Toxicity is more related to exposure than to the dose.
Same dose does not always give the same exposure:
• Differences in exposure routes
• Species/interindividual differences in ADME
• Saturation of effect, repair or detoxification
• Accumulation
• Time (dose x time)
• Interactions (induction, inhibition)
Toxicity is determined by:
1. Characteristics of the compound → (danger/hazard) the compound potentially has an
adverse effect
2. Amount/dose/concentration → degree of exposure to the hazard
LD50: dosage causing death in 50% of exposed animals
Chemical and physical properties
• However: The structure does not always predict activity (SAR)
• There are some (chemical)class specific effects, but most compounds have a unique toxicity
profile
Biological effects (receptor binding, affinity for active center of an enzyme, DNA binding etc)
Dose and systemic exposure
• The amount administered (mg/kg)
• Bioavailability
Exposure of the target organ/tissue/cell
• Administration route
• Metabolite activity
• Transporters in cell membrane
• Blood flow
• Time (chronic exposure)
Individual differences in sensitivity.
, TD50
The dose of a drug necessary to provoke 50% of the maximal toxic effect (in case of the dose-effect
curve)
or
The dose at which 50% of the exposed population shows the toxic effect (in case of a dose-response
curve).
TC50
The (plasma) concentration of a drug necessary to provoke 50% of the toxic effect (in case of the
dose-effect curve)
or
The (plasma) concentration necessary to provoke the toxic effect in 50% of the exposed population
(in case of the dose response curve).
ED50
The dose of a drug necessary to achieve 50% of the desired effect (in case of dose-effect curve)
or
The dose at which 50% of the treated population shows the desired effect (in the case of the dose-
response curve).
EC50
The (plasma) concentration of a drug necessary to achieve 50% of the (desired) effect (in case of
dose-effect curve)
or
The (plasma) concentration at which 50% of the treated population shows the desired effect (in the
case of the dose response curve).
LOAEL: Lowest Observed Adverse Effect Level
The first tested dose/concentration of a drug that gives a significant toxic effect (if a series of
ascending doses / concentrations is tested).
(read out parameter that appeared most sensitive)
NOAEL: No Observed Adverse Effect Level
In a tested series of ascending doses / concentrations, that dose / concentration that is just lower
than the LOAEL
From hazard to risk
Hazard = biological property/potential
Risk = the chance on toxicity
𝑁𝑂𝐴𝐸𝐿
𝐴𝐷𝐼/𝑇𝐷𝐼/𝑅𝑓𝑑 = = 𝑚𝑔/𝑘𝑔 𝑏𝑤/𝑑𝑎𝑦
𝑠𝑎𝑓𝑒𝑡𝑦 𝑓𝑎𝑐𝑡𝑜𝑟
ADI: acceptable daily intake
Safety factor: → interspecies difference = 10
→ interindividual difference = 10
10x10=100
Alle Vorteile der Zusammenfassungen von Stuvia auf einen Blick:
Garantiert gute Qualität durch Reviews
Stuvia Verkäufer haben mehr als 700.000 Zusammenfassungen beurteilt. Deshalb weißt du dass du das beste Dokument kaufst.
Schnell und einfach kaufen
Man bezahlt schnell und einfach mit iDeal, Kreditkarte oder Stuvia-Kredit für die Zusammenfassungen. Man braucht keine Mitgliedschaft.
Konzentration auf den Kern der Sache
Deine Mitstudenten schreiben die Zusammenfassungen. Deshalb enthalten die Zusammenfassungen immer aktuelle, zuverlässige und up-to-date Informationen. Damit kommst du schnell zum Kern der Sache.
Häufig gestellte Fragen
Was bekomme ich, wenn ich dieses Dokument kaufe?
Du erhältst eine PDF-Datei, die sofort nach dem Kauf verfügbar ist. Das gekaufte Dokument ist jederzeit, überall und unbegrenzt über dein Profil zugänglich.
Zufriedenheitsgarantie: Wie funktioniert das?
Unsere Zufriedenheitsgarantie sorgt dafür, dass du immer eine Lernunterlage findest, die zu dir passt. Du füllst ein Formular aus und unser Kundendienstteam kümmert sich um den Rest.
Wem kaufe ich diese Zusammenfassung ab?
Stuvia ist ein Marktplatz, du kaufst dieses Dokument also nicht von uns, sondern vom Verkäufer eliselammers. Stuvia erleichtert die Zahlung an den Verkäufer.
Werde ich an ein Abonnement gebunden sein?
Nein, du kaufst diese Zusammenfassung nur für 6,49 €. Du bist nach deinem Kauf an nichts gebunden.
Kann man Stuvia trauen?
4.6 Sterne auf Google & Trustpilot (+1000 reviews)
45.681 Zusammenfassungen wurden in den letzten 30 Tagen verkauft
Gegründet 2010, seit 14 Jahren die erste Adresse für Zusammenfassungen