Section 14 - Drug Toxicity

Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level Principles of Pharmacology and Toxicology (BIOL3020) Section 14 Drug Toxicity Rang et al 2006 (Chapter 53) Drug Toxicity All drugs can produce harmful and beneficial effects Harmful effects either related or unrelated to mode of action Effects unrelated to mode of action Example thalidomide causing teratogenicity Anaphylaxis from penicillin Liver damage from paracetamol Toxicity Testing  TOXIN-INDUCED CELL DAMAGE AND CELL DEATH Mechanism of TOXIN-INDUCED CELL DAMAGE Usually caused by reactive metabolites of the drug Involves non-covalent and/or covalent interactions with target molecules. Cell death is often via apoptosis rather than caused by acute necrosis.  How do drugs damage cells o  How do drugs damage cells  Glutathione From Berg, Tymoczko and Stryer (2007) Biochemistry How do drugs damage cells  Ca2 Ca2 Hepatotoxicity 2 2 reactive metabolite Liver is no longer able to protect itself from this reactive compound and others Symptoms are nausea and vomiting Acetaminophen poisioning accounts for 35 of cases of severe liver failure From Berg, Tymoczko and Stryer (2007) Biochemistry Covalent Interactions F  Mutagenesis  Biochemical Basis of Mutagenesis Most chemical mutagens act by modifying bases in DNA The O6 and N7 positions of guanine combine covalently with primary carcinogens or reactive metabolites Essential Cell Biology, 2004 Biochemical Basis of Mutagenesis DNA most susceptible when replicating During cell division Developing fetus are susceptible Chemicals may cause teratogenesis  Importance of drugs in mutagenesis has not been firmly established Germ cells in developing females Primary oocytes develop early in embryogenesis In males, cell division in germ cells occurs throughout life Carcinogens Carcinogenic Drugs Few drugs are known carcinogens Pryimethamine mutagenic at high concentrations Methoxsalen carcinogenic and mutagenic used in treatment psoriasis Teratogenesis  Thalidomide introduced in 1957 as a sedative. Was even recommended, specifically for use during pregnancy Teratogenesis Blastocyst Cell division is the main process occurring during blastocyst formation Drugs can cause death of the embryo by inhibiting cell division if embryo survives, subsequent development not seem affected Affected by cytotoxic drugs and possibly ethanol Toxicology Note Fetal Alcohol Syndrome Most common preventable cause of adverse CNS development 4,000-12,000 infants per year in US Characteristics Growth retardation Facial malformations Small head Greatly reduce intelligence Teratogenesis Organogenesis q q Teratogenesis functional maturation Heavy Metal Effects Allergic reactions to drugs