Week 1 Flashcards
Types of Exposure
Intentional Ingestion: drugs, food additives, alcohol, tobacco
(ii) Unintentional: chronic exposure, allergic reactions, chronic toxic effects
(iii) Occupational Exposure: usually chronic inhalation
(lung disease) & skin dermatitis) exposure; acute exposure, accidents
Environmental Exposure: factory effluent (gas liquid-solid), spillages & dumping, continuous release
* exposure to surrounding population (and distant) is generally chronic; long term toxic effects of most industrial chemicals is unknown; most common agents include SO 2 , N2 O, NO2 , CO, pesticide residues
* Acute exposure (industrial accidents - Bhopal and Seveso)
(v) Accidental Poisoning: acute (usually drugs, pesticides, household products, natural poisons)
* Inhalation of fumes from fires
(vi) Intentional Poisoning: homicide, suicide
Occurrence of toxicity depends on
dose, route & rate of adsorption, metabolic changes (Xenobiotic metabolism: activation or inactivation
- Metabolising enzymes are subject to: induction, inhibition, & changes with age, disease, etc.
pharmacogenomics / toxicogenomics)
TD
Toxic dose
LD
Lethal dose
ED
Effective dose
Therapeutic index
LD50/ED50
Hormesis
bi-phasic response
- Low doses can stimulate to <30% of control levels
(by reducing highly-sensitive inhibitory biological processes to
release normal control process)
Rate of absorption depends on
route of exposure: inhalation > oral > dermal
lipophilicity of chemical
Can modify xenobiotic effects in at least 4 ways by forming:
- An inactive metabolite from an active compound
(terminating its bioactivity) - detoxication - An active metabolite from an initially inactive compound (pro-drug to drug; pro-carcinogen to ultimate carcinogen)
- An active metabolite from an initially active compound e.g. Diazepam to Oxazepam, Aldrin to Dieldrin
- A toxic metabolite from an initially active compound
e.g. Sulfathiazole to Acetylsulfathiazole
Xenobiotic Metabolism phase 1
catabolic (oxidation, reduction or hydrolysis)
* introduces a functional chemical group & increases polarity
* Cyt. P450 (CYP) is a major pathway for oxidation
* inducible by many factors (smoking, drinking, drugs, diet)
Compared to the parent xenobiotic, the metabolites are:
* more chemically reactive (sometimes more toxic)
(electrophiles; free radicals)
* more polar from introduction of reactive (functional) group
(e.g. hydroxyl/alcohol group, R-OH) for later conjugation
* more easily eliminated by kidney
Biotransformation affects excretion
Chemical changes occurring with Phase I (oxidation, reduction, hydrolysis) typically
provides a functional group (R-OH) for conjugation in Phase II which ↑ renal excretion
Cytochrome P450
Haem (iron) containing enzymes
* “P” for pink colour as reduced form has Fe2+ combines
with CO -> spectral absorption peak at 450 nm
* Superfamily of related but distinct isoenzymes (more than 70 gene families described) differing in:
- amino acid sequence
- substrate specificity (but overlapping)
- sensitivity to inhibitors and inducing agents
* 3 families involved in many drug reactions:
CYP1, CYP2, CYP3
Xenobiotic Metabolism phase II
synthetic, anabolic (conjugation to glutathione
(GSH), sulfate, glucuronide, amino acids, etc.)
* conjugates a highly polar compound to greatly ↑ excretion Compared to Phase I metabolites the Phase II conjugate is:
* usually less active or inactive
* much more polar & more easily eliminated by kidney
Other protective factors:
antioxidants (Vit. E, Vit. C, sulfhydryls, e.g. GSH)
Toxic outcome depends on: Activation vs. Detoxication
glutathione ‘GSH’
Major protection against
oxidants in biological
systems
Factors Affecting Drug Metabolism
Polymorphisms (SNPs) - genes for Phase I (CYPs 2D6, 2C9, 2C19) & Phase II (UGT1A1, NAT2, COMT) -> poor or rapid metabolism
* Disease - organ damage will compromise metabolic functions
- many cytokines released during inflammation downregulate liver
CYP expression (except CYP2A6)
* Age - many enzyme activities are low in fetus & neonates, increase in adulthood, then decrease again with age (decreased liver size & blood flow -> declining metabolism)
* Gender - sex hormone-dependent expression of certain enzymes
involved in sex steroid synthesis & metabolism (CYP3A4, CYP19)
* Pregnancy - ↑ some Phase I (CYPs 3A4, 2D6, 2C9) & Phase II (UGT 1A4, 2B7) enzymes, BUT ↓some other CYPs (1A2, 2C19)
